Ex vivo organ care system

ABSTRACT

The invention generally relates to systems, methods, and devices for ex vivo organ care. More particularly, in various embodiments, the invention relates to caring for a liver ex vivo at physiologic or near-physiologic conditions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/728,771 filed Jun. 2, 2015, issued as U.S. Pat. No. 10,076,112; whichclaims the benefit under 35 U.S.C. § 119(e), of provisional applicationU.S. Ser. No. 62/006,871, filed Jun. 2, 2014, entitled, “EX VIVO ORGANCARE SYSTEM”, and U.S. Ser. No. 62/006,878, filed Jun. 2, 2014,entitled, “EX VIVO ORGAN CARE SYSTEM”, the entire subjects of which areincorporated herein by reference.

FIELD OF THE INVENTION

The invention generally relates to systems, methods, and devices for exvivo organ care. More particularly, in various embodiments, theinvention relates to caring for an organ ex vivo at physiologic ornear-physiologic conditions.

BACKGROUND

Current organ preservation techniques typically involve hypothermicstorage of the organ packed in ice along with a chemical perfusatesolution. In the case of a liver transplant, tissue damage resultingfrom ischemia can occur when hypothermic techniques are used to preservethe liver ex vivo. The severity of these injuries can increase as afunction of the length of time the organ is maintained ex-vivo. Forexample, continuing the liver example, typically it may be maintainedex-vivo for about seven hours before it becomes unusable fortransplantation. This relatively brief time period limits the number ofrecipients who can be reached from a given donor site, therebyrestricting the recipient pool for a harvested liver. Even within thistime limit, the liver may nevertheless be significantly damaged. Asignificant issue is that there may not be any visible indication of thedamage. Because of this, less-than-optimal organs may be transplanted,resulting in post-transplant organ dysfunction or other injuries. Thus,it is desirable to develop techniques that can extend the time duringwhich an organ such a liver can be preserved in a healthy state ex-vivoand enable assessment capabilities. Such techniques would reduce therisk of transplantation failure and enlarge potential donor andrecipient pools.

SUMMARY

The below summary is exemplary only, and not limiting. Other embodimentsof the disclosed subject matter are possible.

Embodiments of the disclosed subject matter can provide techniquesrelating to portable ex vivo organ care, such as ex vivo liver organcare. In some embodiments, the liver care system can maintain the liverat, or near, normal physiological conditions. To this end, the systemcan circulate an oxygenated, nutrient enriched perfusion fluid to theliver at or near physiological temperature, pressure, and flow rate. Insome embodiments, the system employs a blood product-based perfusionfluid to more accurately mimic normal physiologic conditions. In otherembodiments, the system uses a synthetic blood substitute solution,while in still other embodiments, the solution can contain a bloodproduct in combination with a blood substitute product.

Some embodiments of the disclosed subject matter relate to a method forusing lactate and liver enzyme measurements to evaluate the: i) overallperfusion status of an isolated liver, ii) metabolic status of anisolated liver, and/or iii) the overall vascular patency of an isolateddonor liver. This aspect of the disclosed subject matter is based on theability of liver cells to produce/generate lactate when they are starvedfor oxygen and metabolize/utilize lactate for energy production whenthey are well perfused with oxygen.

Some embodiments of the organ care system can include a module that hasa chassis, and an organ chamber assembly that is mounted to the chassisand is adapted to contain a liver during perfusion. The organ caresystem can include a fluid conduit with a first interface for connectingto an hepatic artery of the liver, a second interface for connecting tothe portal vein, a third interface for connecting to the inferior venacava and a fourth interface to connect to the bile duct. The organ caresystem can include a lactate sensor for sensing lactate in the fluidbeing provided to and/or flowing from the liver. The organ care systemcan also include sensors for measuring the pressures and flows of thehepatic artery, portal vein, and/or inferior vena cava.

Some embodiments can relate to a method of determining liver perfusionstatus. For example, a method for evaluating liver perfusion status caninclude the steps of placing a liver in a protective chamber of an organcare system, pumping a perfusion fluid into the liver, providing a flowof the perfusion fluid away from the liver, measuring the lactate valueof the fluid leading away from the liver, measuring the amount of bileproduced by the liver, and evaluating the status of the liver using themeasured lactate values, oxygen saturation level, and/or the quantityand quality of bile produced.

Some embodiments can relate to a method for providing a physiologic rateof flow and a physiologic pressure for both the hepatic artery and forthe portal vein. In some embodiments the flow is sourced by a singlepump. In particular, the system can include a mechanism for the user tomanually divide a single source of perfusate to the hepatic artery andportal vein, and to adjust the division for physiologic flow rates andpressures. In other embodiments the system automatically divides thesingle source of perfusate flow to the hepatic artery and portal vein toresult in physiologic pressures and rates of flow using, for example, anautomatic control algorithm.

Some embodiments of the organ care system can include a nutritionalsubsystem that infuses the perfusion fluid with a supply of maintenancesolutions as the perfusion fluid flows through the system, and in someembodiments, while it is in the reservoir. According to one feature, themaintenance solutions include nutrients. According to another feature,the maintenance solutions include a supply of therapeutics and/oradditives to support extended preservation (e.g., vasodilators, heparin,bile salts, etc.) for reducing ischemia and/or other reperfusion relatedinjuries to the liver.

In some embodiments, the perfusion fluid includes blood removed from thedonor through a process of exsanguination during harvesting of theliver. Initially, the blood from the donor is loaded into the reservoirand the cannulation locations in the organ chamber assembly are bypassedwith a bypass conduit to enable normal mode flow of perfusion fluidthrough the system without a liver being present, aka “priming tube”.Prior to cannulating the harvested liver, the system can be primed bycirculating the exsanguinated donor blood through the system to warm,oxygenate and/or filter it. Nutrients, preservatives, and/or othertherapeutics may also be provided during priming via the infusion pumpof the nutritional subsystem. During priming, various parameters mayalso be initialized and calibrated via the operator interface. Onceprimed and running appropriately, the pump flow can be reduced or cycledoff, the bypass conduit can be removed from the organ chamber assembly,and the liver can be cannulated into the organ chamber assembly. Thepump flow can be restored or increased, as the case may be.

In some embodiments, the system can include a plurality of compliancechambers. The compliance chambers are effectively small inline fluidaccumulators with flexible, resilient walls for simulating the humanbody's vascular compliance. As such, they can aid the system in moreaccurately mimicking blood flow in the human body, for example, byfiltering/reducing fluid pressure spikes due, for example, to flow ratechanges. In one configuration, compliance chambers are located in theperfusate path to the portal vein and on the output of the perfusionfluid pump. According to one embodiment, a compliance chamber is locatednext to a clamp used for regulating pressure to effect physiologichepatic artery and portal vein flows.

In some embodiments, the organ chamber assembly includes a pad or a sacassembly sized and shaped for interfitting within a bottom of thehousing. Preferably, the pad assembly includes a pad formed from amaterial resilient enough to cushion the organ from mechanicalvibrations and shocks during transport. In the case of the organ chamberassembly being configured to receive a liver, according to one feature,the pad of the invention includes a mechanism to conform the pad todifferently sized and shaped livers so as to constrain them from theeffects of shock and vibration encountered during transport.

Some embodiments of the organ care system are divided into a multipleuse module and a single use module. The single use module can be sizedand shaped for interlocking with the portable chassis of the multipleuse module for electrical, mechanical, gas and fluid interoperation withthe multiple use module. According to one embodiment, the multiple andsingle use modules can communicate with each other via an opticalinterface, which comes into optical alignment automatically upon thesingle use disposable module being installed into the portable multipleuse module. According to another feature, the portable multiple usemodule can provide power to the single use disposable module via springloaded connections, which also automatically connect upon the single usedisposable module being installed into the portable multiple use module.According to one feature, the optical interface and spring loadedconnections can ensure that connection between the single and multiplemodules is not lost due to jostling, for example, during transport overrough terrain.

In some embodiments, the disposable single-use module includes aplurality of ports for sampling fluids from the perfusate paths. Theports can be interlocked such that sampling fluid from a first of theplurality of ports prohibits simultaneously sampling fluids from asecond port of the plurality. This safety feature reduces the likelihoodof mixing fluid samples and inadvertently opening the ports. In oneembodiment, the single use module includes ports for sampling from oneor more of the hepatic artery, portal vein, and/or IVC interfaces.

Some embodiments of the disclosed subject matter are directed at amethod of providing therapy to a liver. Exemplary methods can includeplacing a liver in a protective chamber of a portable organ care system,pumping a perfusion fluid into the liver via a hepatic artery and portalvein, providing a flow of the perfusion fluid away from the liver viathe vena cava, operating a flow control to alter a flow of the perfusionfluid such that the perfusion fluid is pumped into the liver via ahepatic artery and portal vein and flows away from the liver via a venacava, and administering a therapeutic treatment to the liver. Thetreatments can include, for example, administering one or more ofimmunosuppressive treatment, chemotherapy, gene therapy and irradiationtherapy to the liver. Other treatments may include surgical applicationsincluding split transplant and cancer resection.

In some embodiments, the disclosed subject matter can include aperfusion circuit for perfusing a liver ex-vivo, the perfusion circuitincluding a single pump for providing pulsatile fluid flow of aperfusion fluid through the circuit; a gas exchanger; a dividerconfigured to divide the perfusion fluid flow into a first branch and asecond branch; wherein the first branch is configured to provide a firstportion of the perfusion fluid to a hepatic artery of the liver at ahigh pressure and low flow rate, wherein the first branch is in fluidpressure communication with the pump; wherein the second branch isconfigured to provide the remainder of the perfusion fluid to a portalvein of the liver at a relatively low pressure and high flow rate,wherein the second branch is in fluid pressure communication with thepump; the second branch further comprising a clamp located between thedivider and the liver for selectively controlling the flow of perfusionfluid to the portal vein; the second branch further comprising acompliance chamber between the divider and the liver configured toreduce the pulsatile flow characteristics of the perfusion fluid fromthe pump to the portal vein; wherein the pump is configured tocommunicate fluid pressure through the first and second branches to theliver; a drain configured to receive perfusion fluid from anuncannulated inferior vena cava of the liver; and a reservoir positionedentirely below the liver and located between drain and the pump,configured to receive the perfusion fluid from the drain and store avolume of fluid. Other embodiments are possible.

In some embodiments, the disclosed subject matter can include a solutionpump including a stepper motor in communication with a threaded rod; acarriage that is connected to the rod and configured to move along alinear axis as the rod rotates, the carriage being configured tocompress a plunger of a syringe when moved in a first direction andbeing configured to retract the plunger of the syringe when moved in asecond direction; a clamp configured to connect to the plunger; aconnection assembly including a port configured to couple to a tip ofthe syringe; a first one way valve configured to allow fluid to flowinto the syringe through the port as the syringe is retracted; a secondone way valve configured to allow fluid to flow away from the syringethrough the port as the syringe is compressed; a pressure sensor coupledto the connection assembly for determining a pressure of the fluidwithin the connection assembly; a controller configured to controloperation of the stepper motor; and a sensor configured to determinewhen the syringe is fully retracted. Other embodiments are possible.

In some embodiments, the disclosed subject matter can include a methodincluding rotating a rod to cause a carriage connected to the rod tomove along a linear axis of the rod, compressing a plunger of a syringeas the carriage moves in a first direction along the linear axis,delivering fluid from the syringe into a port of a connection assemblyand through a first one-way valve as the plunger is compressed,retracting a plunger of a syringe as the carriage moves in a seconddirection along the linear axis, delivering fluid to the syringe througha second one-way valve, and through the port of the connection assemblyas the plunger is retracted, sensing a pressure of fluid in theconnection assembly, and sensing a location of the plunger when thesyringe is retracted. Other embodiments are possible.

In some embodiments, the disclosed subject matter can include an ex-vivoperfusion liquid for machine perfusion of donor livers comprising anenergy-rich component, a bile salt, an electrolyte, and a bufferingcomponent. The liquid can include a blood product. The energy-richcomponent can be one or more compounds selected from the groupconsisting of a carbohydrate, pyruvate, flavin adenine dinucleotide(FAD), ß-nicotinamide adenine dinucleotide (NAD), ß-nicotinamide adeninedinucleotide phosphate (NADPH), a phosphate derivative of nucleoside, acoenzyme, and metabolite and precursor thereof. The liquid furtherincludes one or more components selected from the group consisting of ananti-clotting agent, a lipid, cholesterol, a fatty acid, oxygen, anamino acid, a hormone, a vitamin, and a steroid. The perfusion solutionis essentially free of carbon dioxide. Other embodiments are possible.

These and other embodiments of the disclosed subject matter will be morefully understood after a review of the following figures, and detaileddescription.

BRIEF DESCRIPTION OF THE FIGURES

The following drawings are intended show non-limiting examples of thedisclosed subject matter. Other embodiments are possible.

FIG. 1 is an exemplary diagram of a liver.

FIG. 2 is a photograph of an exemplary single use module.

FIGS. 3A-3I show various views of an exemplary organ care system andcomponents thereof.

FIG. 4 shows an exemplary system that can be used within an embodimentof the organ care system.

FIG. 5 shows an exemplary system that can be used within an embodimentof the organ care system.

FIGS. 6A-6E show an exemplary pump configuration that can be used withinan embodiment of the organ care system.

FIGS. 7A-7Q show an exemplary solution infusion pump that can be usedwithin an embodiment of the organ care system.

FIG. 8 shows an exemplary system that can be used within an embodimentof the organ care system.

FIG. 9 shows an exemplary system that can be used within an embodimentof the organ care system.

FIG. 10 shows an exemplary system that can be used within an embodimentof the organ care system.

FIG. 11 shows an exemplary system that can be used within an embodimentof the organ care system.

FIGS. 12A-12G show exemplary graphical user interfaces that can be usedwithin an embodiment of the organ care system.

FIG. 12H shows an exemplary system that can be used within an embodimentof the organ care system.

FIGS. 13A-13R show exemplary embodiments of a single use module andcomponents thereof that can be used in an embodiment of the organ caresystem.

FIGS. 14A-14S show exemplary embodiments of an organ chamber andcomponents thereof that can be used in an embodiment of the organ caresystem.

FIGS. 15A-15D show an exemplary embodiment of a support structure thatcan be used in an embodiment of the organ care system.

FIGS. 16A-16J show an exemplary pad and components thereof and aflexible material support surface that can be used in embodiments of theorgan care system.

FIG. 17 shows an exemplary system that can be used within an embodimentof the organ care system.

FIG. 18A-18G show an exemplary heater assembly and components thereofthat can be used within an embodiment of the organ care system.

FIG. 19A-19C show an exemplary sensor system that can be used within anembodiment of the organ care system.

FIGS. 20A-20C show an exemplary system that can be used within anembodiment of the organ care system.

FIGS. 21A-21K show exemplary hepatic artery cannulas that can be usedwithin an embodiment of the organ care system.

FIGS. 22A-22G show exemplary portal vein cannulas that can be usedwithin an embodiment of the organ care system.

FIGS. 23A-23N show an exemplary connector that can be used within anembodiment of the organ care system.

FIGS. 24A-24L show an exemplary connector that can be used within anembodiment of the organ care system.

FIGS. 25A-25D show exemplary clamps that can be used within anembodiment of the organ care system.

FIGS. 26-27 show exemplary processes that can be used in embodiments ofan organ care system.

FIG. 28 shows exemplary test results from an embodiment of an organ caresystem.

FIG. 29 shows an exemplary process that can be used in embodiments of anorgan care system.

FIG. 30 shows exemplary systems that can be used within an embodiment ofthe organ care system.

FIG. 31 shows the hepatic artery flow (HAF) trend throughout the courseof 8 hours preservation on OCS.

FIG. 32 shows the portal vein flow (PVF) trend throughout the course of8 hours preservation on OCS.

FIG. 33 shows a graphical depiction of hepatic artery pressure versusportal vein pressure throughout the 8 hour OCS-liver perfusion.

FIG. 34 is a graphical depiction of arterial lactate levels over the 8hour OCS liver perfusion.

FIG. 35 is a graphical depiction of total bile production over the 8hour OCS liver perfusion.

FIG. 36 is a graphical depiction of AST level over the 8 hour OCS liverperfusion.

FIG. 37 is a graphical depiction of ACT level over the 8 hour OCS liverperfusion.

FIG. 38 is a graphical depiction of oncotic pressure throughout thecourse of 8 hours preservation on OCS.

FIG. 39 is a graphical depiction of bicarb levels over the 8 hour OCSliver perfusion.

FIG. 40 is a depiction of the detected pH levels throughout the courseof 8 hours preservation on OCS.

FIG. 41 shows images of tissues taken from samples in Phase I, Group A.

FIG. 42 depicts Hepatic Artery Flow of a 12 hr OCS Liver Perfusion.

FIG. 43 depicts Portal Vein Flow of a 12 hr OCS Liver Perfusion.

FIG. 44 depicts Hepatic Artery Pressure vs. Portal Vein Pressure in a 12hr OCS-Liver Perfusion.

FIG. 45 depicts Arterial Lactate in a 12 hr OCS-Liver Perfusion.

FIG. 46 depicts Bile Production in a 12 hr OCS-Liver Perfusion.

FIG. 47 depicts AST Level of a 12 hr OCS-Liver Perfusion.

FIG. 48 depicts ACT Levels in a 12 hr OCS-Liver Perfusion.

FIG. 49 depicts Hepatic Artery Flow on a simulated transplant OCS-Liverpreservation arm vs. a simulated transplant control cold preservationarm.

FIG. 50 depicts Portal Vein Flow on a simulated transplant OCS-Liverpreservation arm vs. a simulated transplant control cold preservationarm.

FIG. 51 depicts Hepatic Artery Pressure vs. Portal Vein Pressure in asimulated transplant OCS-Liver preservation arm vs. a simulatedtransplant control cold preservation arm.

FIG. 52 depicts Arterial Lactate on a simulated transplant OCS-Liverpreservation arm vs. a simulated transplant control cold preservationarm.

FIG. 53 depicts bile production of a simulated transplant OCS-Liverpreservation arm vs. a simulated transplant control cold preservationarm.

FIG. 54 depicts a AST Level of simulated transplant OCS-Liverpreservation arm vs. a simulated transplant control cold preservationarm.

FIG. 55 depicts ACT Levels of a simulated transplant OCS-Liverpreservation arm vs. a simulated transplant control cold preservationarm.

FIG. 56 depicts oncotic pressure of a simulated transplant OCS-Liverpreservation arm vs. a simulated transplant control cold preservationarm.

FIG. 57 depicts the Bicarb Level of a simulated transplant OCS-Liverpreservation arm vs. a simulated transplant control cold preservationarm.

FIG. 58 depicts pH Levels of a simulated transplant OCS-Liverpreservation arm vs. a simulated transplant control cold preservationarm.

FIG. 59 shows the histological examination of Parenchymal tissue andBile duct tissue.

FIG. 60 shows the histological examination of Parenchymal tissue andBile duct tissue.

FIG. 61 is a diagram illustrating locations of samples from a liver of apig.

FIG. 62 illustrates the Hepatic Artery Pressure (HAP) trend over thecourse of 24 hours perfusion on the OCS.

FIG. 63 illustrates the Portal Vein Pressure in an OCS-LiverPreservation arm vs the control Cold preservation arm.

FIG. 64 illustrates a Hepatic Artery Flow in a OCS-Liver Preservationarm vs. control Cold preservation arm.

FIG. 65 illustrates a Portal Vein Flow in an OCS-Liver Preservation armvs. control Cold preservation arm.

FIG. 66 depicts Arterial Lactate in an OCS-Liver Preservation arm vs. acontrol Cold preservation arm.

FIG. 67 illustrates an AST Level OCS-Liver Preservation arm vs. controlCold Preservation arm.

FIG. 68 illustrates an ALT Level OCS-Liver Preservation arm vs. controlCold preservation arm.

FIG. 69 depicts a GGT Level of an OCS-Liver Preservation arm vs. controlCold preservation arm.

FIG. 70 depicts a PH level of an OCS-Liver Preservation arm vs. acontrol Cold preservation arm.

FIG. 71 depicts a HCO3 level in an OCS-Liver Preservation arm vs. aControl Cold preservation arm.

FIG. 72 depicts a bile production OCS-Liver Preservation arm vs. controlCold preservation arm. FIG. 72 demonstrates that both arms maintainedbile production rate of >10 ml/hr.

DETAILED DESCRIPTION

While the following description uses section headings, these areincluded only as a convenience to the reader. The section headings arenot intended to be limiting or impose any restriction on the subjectmatter herein. For example, components described in one section of thedescription can be included in other sections additionally oralternatively. The embodiments disclosed herein are exemplary only andit is within the scope of the present disclosure that the disclosedembodiments and various features may be interchanged with one another.

I. INTRODUCTION

A. General Summary

Embodiments of the disclosed subject matter can provide techniques formaintaining a liver ex vivo, such as during a transplant procedure. Thesystem can maintain a liver in conditions mimicking the human body. Forexample, the system can supply a blood substitute to an ex vivo liver ina manner that simulates the blood flow provided by the body. Morespecifically, the system can provide a flow of blood substitute to ahepatic artery and portal vein of a liver having flow and pressurecharacteristics similar to the human body. In some embodiments, thedesired flows can be achieved using a pumping system that employs asingle pump. The system can also warm the blood substitute to anormothermic temperature that simulates the human body and can providenutrients to the blood substitute to maintain the liver and to promotethe normal generation of bile by the liver. By performing thesetechniques, the length of time that a liver can be maintained outsidethe body can be extended, thereby making the geographical distancebetween donors and recipients less important than it previously was.Also, some of the embodiments disclosed herein that are used to maintainthe liver ex vivo can also be used to assess the condition of the liverpre-transplant. In some embodiments, the techniques described herein canalso be used to treat an injured and/or diseased liver ex vivo usingtreatments that would otherwise be harmful to the body if performed invivo. Other embodiments are within the scope of the disclosed subjectmatter.

While the disclosure herein focuses on embodiments that are intended tomaintain or treat a liver, the disclosure is not limited as such. Forexample, techniques described herein can also be used, or can be adaptedfor use with other organs such as lungs, a heart, intestines, apancreas, a kidney, a spleen, a bladder, a gallbladder, a stomach, skin,and a brain.

II. LIVER COMPARED WITH OTHER ORGANS

While the liver is one of many organs in the human body, the liver canpresent challenges during ex vivo maintenance and transport that do notexist with other organs such as the heart and lungs. Some exemplarydifferences and considerations are described next.

A. Liver Uses Two Perfusate Inflow Supplies

Importantly, the liver uses two unique input paths for perfusate ascompared with only one for other organs. Hepatic circulation is uniqueas featured by its dual vascular blood supply, each having differentflow characteristics. Referring to FIG. 1, which is an exemplaryconceptual drawing of a liver 100, the liver uses two blood supplies,the portal vein 10 and the hepatic artery 12. In particular, the hepaticartery delivers blood to the liver having high pressure, pulsatile flow,but of relatively low flow rate. Hepatic blood flow typically accountsfor about one-third of the total liver blood flow. The portal veindelivers blood to the liver having a low pressure and minimalpulsatility at a higher flow rate. Portal vein flow typically accountsfor about two-thirds of the total blood flow to the liver.

The dual blood supply expected by the liver can present challenges whenone tries to artificially supply physiologic blood flow thereto when theorgan is in an ex vivo system. While the challenges can be difficultwhen using a dual-pump design, they can be intensified when using asingle-pump design. Some embodiments of the subject matter disclosedherein can address these challenges.

B. Assisted Drainage of Blood

In vivo, the liver is positioned beneath the diaphragm. Due to thispositioning, liver blood flow and venous drainage via the inferior venacava 14 is typically enhanced by diaphragmatic contraction as a resultof pressure exerted on the liver. When the diaphragm moves in tandemwith the lungs as air is drawn in and expelled by the lungs, themovement of the diaphragm can act on the liver by applying pressure tothe organ, thereby pushing blood out of the tissue. It is desirable tomimic this phenomenon in an ex-vivo liver to help encourage blood flowout of the liver and prevent blood buildup in the organ.

C. Oncotic Pressure

To minimize edema formation in an ex vivo liver, the perfusate shouldhave high oncotic pressure, for example, dextran, 25% albumin, and/orfresh frozen plasma. In some embodiments, oncotic pressure of thecirculating perfusate is maintained between 5-35 mmHg, and morespecifically between 15-25 mmHg. Non-limiting examples of possibleoncotic pressures are 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25mmHg, or any ranges bounded by the values noted here.

D. Metabolism and CO₂ Levels

The liver is a metabolic hub in the body and is in a constant state ofmetabolism. Most compounds absorbed by the intestine first pass throughthe liver, which is thus able to regulate the level of many metabolitesin the blood. For example, the conversion of sugars into fat and otherenergy stores (e.g., gluconeogenesis and glycolysis) results inproduction of CO₂. The liver consumes about 20% of the total bodyoxygen. As a result, the liver produces higher levels of CO₂ than mostother organs. In vivo, the organ is able to self-regulate to removeexcess carbon dioxide from the organ. However, for an ex-vivo organ, itcan be desirable to remove excess carbon dioxide from the organ tomaintain physiologic levels of oxygen and carbon dioxide and thus pH.The system described in this application can facilitate establishment ofblood chemistry equilibrium suitable for organ preservation ex vivo.

E. Bile Production

The liver is an excrement producing organ. The excrement, bile, isusually produced and excreted by the organ in vivo. Bile is produced inthe liver by hepatocytes. In vivo, the liver utilizes bile salts tocreate bile, and bile salts are recycled through the enterohepaticcirculation system back to the liver to be reused. The bile salts inturn stimulate the hepatocytes to produce more bile. Ex vivo, bile saltsare not recycled back to the liver. As a result, it can be desirable tosupplement perfusate with bile salts to aid the organ in producing bile.Additionally, in some instances, the bile produced by the liver canprovide an indication (e.g., quantity, color and consistency) of thesuitability of the organ for transplant.

F. Supporting a Liver

The liver is the largest solid organ in the body, but it is delicate andfragile. In the body, it is protected by the rib cage and other organs.Unlike many other organs, the liver does not include protective elementsand is not defined by a rigid structure. Therefore, when the liver isremoved from the body and maintained ex-vivo, it should be treated moredelicately than other organs. For example, it can be desirable toprovide proper support for the liver, place the liver on a low frictionsurface, and/or cover the organ with a wrap to protect the organ fromdamage during transport and while being maintained ex vivo.

G. Perfusate

Given the liver's wide range of vital functions when compared with otherorgans (e.g., detoxification, protein synthesis, glycogen storage, andproduction of biochemicals necessary for digestion), the perfusion fluidused in the organ care system described herein can be specially designedto maintain the liver in close to its physiological state to maintainits regular functions. For instance, because the liver is in a constantstate of metabolism consuming energy, the oxygen content in theperfusion fluid can be maintained at close to or more than thephysiological level to meet its high demand as a metabolic warehouse.Similarly, the perfusion fluid can also be designed to includesufficient concentration of energy-rich components, such ascarbohydrates and electrolytes, to provide the liver with an energysource to carry out its functions.

The flow rate of the perfusion fluid can be also properly adjusted toensure that oxygen and nutrients are delivered to an ex vivo liver at asuitable rate. Furthermore, the carbon dioxide content in the perfusionliquid can be lower than the level in physiological state, thus furtherdriving the equilibrium of the liver's biological reactions tometabolism and oxidation. In some embodiments, the perfusion fluid usedherein does not contain significant amount of carbon dioxide or is freefrom all carbon dioxide. In some embodiments, the perfusion fluid usedherein also contains sufficient amount of bile salt to sustain the needof the liver to produce bile. Thus, the perfusion fluid for the organcare system described herein can be designed to maintain the liver'sregular cellular functions to maintain the liver in a viable state.

III. DESCRIPTION OF EXEMPLARY SYSTEM COMPONENTS

A. General Architecture

FIG. 3 shows an exemplary organ care system 600 that can be used topreserve an organ such as a liver when the organ is ex vivo during, forexample, a transplant operation or medical procedure. At a generallevel, the organ care system 600 is configured to provide conditions toan ex vivo organ that mimic the conditions the organ experiences when invivo. For example, in the case of a liver, the organ care system 600 canprovide a perfusate flow to the organ in a manner that mimics blood flowin a human body (e.g., flow, pressure, and temperature) and providesimilar environmental characteristics (e.g., temperature).

In some embodiments, the organ care system 600 can be divided into twoparts: a disposable single-use portion (e.g., 634) and a non-disposablemultiple-use portion (e.g., 650) (also referred to herein as asingle-use module and a multiple-use module). As the names imply, thesingle-use portion can be replaced after a liver is transported and themultiple-use portion can be reused. At a general level, though notrequired, the single-use portion includes those portions of the systemthat come into direct contact with biological material whereas themultiple-use portion includes those components that do not come intocontact with biological material. In some embodiments, all of thecomponents in the single-use portion are sterilized before use, whereasthe components in the multiple-use portion are not. Each of the portionsare described in detail below. This configuration allows a method ofoperation where, after use, the entire single-use module 634 can bediscarded and replaced with a new single-use module. This can allow thesystem 600 to be available for use again after a short turnaround time.

Typically the single and multiple use portions can be configured to beremovably connected to one another via a mechanical interface.Additionally, the single and multiple use portions can includemechanical, gas, optical, and/or electrical connections to allow the twoportions to interact with one another. In some embodiments, theconnections between the portions are designed to beconnected/unconnected from one another in a modular fashion.

The disposable module 634 and the multiple use module 650 can beconstructed at least in part of material that is durable yetlight-weight such as polycarbonate plastic, carbon fiber epoxycomposites, polycarbonate ABS-plastic blend, glass reinforced nylon,acetal, straight ABS, aluminum, and/or magnesium. In some embodiments,the weight of the entire system 600, is less than 100 pounds, includingthe multiple use module, organ, batteries, gas tank, and priming,nutritional, preservative and perfusion fluids, and less than about 50pounds, excluding such items. In some embodiments, the weight of thesingle use module 634 is less than 12 pounds, excluding any solutions.In some embodiments, the multiple use module, excluding all fluids,batteries, and gas supply, weighs less than 50 pounds.

With the cover removed and the front panel open, an operator can haveeasy access to many of the components of the disposable 634 and multipleuse 650 modules. For example, the operator can access the variouscomponents of the single and multiple use modules and can install and/orremove the single use module from to/from the multiple use module.

While certain components are described herein as being in the single-useportion or the multiple-use portion of the system 600, this is exemplaryonly. That is, components identified herein as being located in thesingle-use portion can also be located in the multiple-use portion andvice-versa.

B. Exemplary Multiple Use Module

Referring to FIGS. 3A-3I, the multiple use module can include severalcomponents including a housing, a cart, a battery, a gas supply, atleast part of a perfusion fluid pump, an infusion pump, and a controlsystem.

1. Cart/Housing

Referring to FIGS. 3A-3I, an exemplary embodiment of the organ caresystem is shown as organ care system 600 can include a housing 602 and acart 604. The cart 604 can include a platform and wheels fortransporting the system 600 from place to place. A latch 603 can securethe housing 602 to the cart 604. To further aid in portability, thesystem 600 can also include a handle hinge mounted to the left side ofthe housing 602, along with two rigidly mounted handles 612 a and 612 bmounted on the left and right sides of the housing 602. The housing 602can further include a removable top lid (not shown) and a front panel615 hinged to a lower panel by hinges 616 a and 616 b. The cover caninclude handles for aiding with removal.

The system 600 can include an AC power cable 618, along with a frame forsecuring the power cable, both which can be located on the lower sectionof the left side of the housing 602. A power switch 622, which can alsolocated on the lower section of the left side, can enable an operator torestart the system software and electronics.

FIG. 3G shows a front perspective view of the multiple use module 650with the single use module 634 removed. As shown, the multiple usemodule 650 can include the cart 604 and the housing 602, along with allof the components mounted to/in it. The multiple use module 650 alsoincludes a bracket assembly 638 for receiving and locking into place thesingle use module 634. An exemplary bracket assembly 638 is shown inFIG. 3H.

In some embodiments, the housing 602 can include a fluid tight basin,which is configured to capture any perfusion fluid and/or any otherfluid that may inadvertently leak from the upper portion of the housing602 and prevent it from reaching the lower section of the housing 602.Thus, in some embodiments, the basin can shield the electroniccomponents of the system 600 from leaked fluid. In some embodiments, thebasin 652 can be sized to accommodate the entire volume of fluids usedin the system 600 at any particular time.

The system 600 can also include the operator interface module 146, alongwith a cradle 623 for holding the operator interface module 146. Theoperator interface module 146 can include a display 624 for displayinginformation to an operator. The operator interface module 146 can alsoinclude a rotatable and depressible knob 626 for selecting betweenmultiple parameters and display screens. The knob 626 can also be usedto set parameters for automatic control of the system 600, as well as toprovide manual control over the operation of the system 600. In someembodiments, the operator interface module 146 can include its ownbattery and may be removed from the cradle 623 and used in a wirelessmode. While in the cradle 623, power connections can enable the operatorinterface module 146 to be charged. The operator interface module canalso include control buttons for controlling the pump, silencing ordisabling alarms, entering or exiting standby mode, and starting theperfusion clock, which initiates the display of data obtained duringorgan care.

Referring also to FIG. 5, the system 600 can also include a plurality ofinterconnected circuit boards for facilitating power distribution anddata transmission to, from and within the system 600. For example, themultiple use module 650 can include a front end interface circuit board636, which optically and electromechanically couples to the front endcircuit board 637 of the single use module 650. The system 600 canfurther include a main board 718, a power circuit board 720, and abattery interface board 711 located on the multiple use module 650. Themain board 718 can be configured to allow the system 600 to be faulttolerant, in that if a fault arises in the operation of a given circuitboard, the main board 718 can save one or more operational parameters(e.g., pumping parameters) in non-volatile memory. When the system 600reboots, it can then re-capture and continue to perform according tosuch parameters. Additionally, the system 600 can divide criticalfunctions among multiple processors so that if one processor fails theremaining critical functions can continue to be served by the otherprocessors.

2. Power System

Referring also to FIG. 4, the multiple-use portion of the system 600 caninclude a power subsystem 148 that is configured to provide power to thesystem 600. The power subsystem 148 can provide power to the system 600using swappable batteries and/or an external power source. In someembodiments, the power subsystem 148 can be configured to switch betweenexternal power and an onboard battery, without interruption of systemoperation. The power subsystem 148 can also be configured toautomatically allocate externally supplied power between powering thesystem 600, charging the batteries, and charging internal batteries ofthe operator interface module 146. The batteries in the power system canbe used as the primary power source and/or as a backup power source inthe event the external power source fails or becomes insufficient.Additionally, the power system 148 can be configured to be compatiblewith multiple types of external power sources. For example, the powersystem can be configured to receive multiple input voltages (e.g.,100V-230V), multiple frequencies (e.g., 50-60 Hz), single phase power,three-phase power, AC, and/or DC power. Additionally, in someembodiments the operator interface module 146 can have its own battery368.

The housing 602 can include a battery bay 628 that is configured to holdone or more batteries 352. In embodiments with more than one battery,the battery bay 628 can also include a lockout mechanism 632 that isconfigured to prevent more than one battery from being removed from thebattery bay 628 at any given time while the system 600 is operating.This feature can provide an additional level of fault tolerance to helpensure that a source of power is always available. The system 600 canalso include a tank bay 630 that can be configured to receive one ormore tanks of gas.

Referring to the conceptual drawing of FIG. 5 cabling 731 can bringpower (such as AC power 351) from a power source 350 to the powercircuit board 720 by way of connectors 744 and 730. The power supply 350can convert the AC power to DC power and distribute the DC power asdescribed above. The power circuit board 720 can couple DC power and adata signal 358 via respective cables 727 and 729 from the connectors726 and 728 to corresponding connectors 713 and 715 on the front endinterface circuit board 636. Cable 729 can carry both power and a datasignal to the front end interface board 636. Cable 727 can carry powerto the heater 110 via the front-end interface board 636. The connectors713 and 715 can interfit with corresponding connectors 712 and 714 onthe front end circuit board 637 on the single use module 634 to providepower to the single use module 634.

7The power circuit board 720 can also provide DC power 358 and a datasignal from the connectors 732 and 734, respectively, on the powercircuit board 720 to corresponding connectors 736 and 738 on the maincircuit board 718 by way of the cables 733 and 735. The cable 737 cancouple DC power 358 and a data signal from a connector 740 on the maincircuit board 718 to the operator interface module 146 by way of aconnector 742 on the operator interface module cradle 623. The powercircuit board 720 can also provide DC power 358 and a data signal fromconnectors 745 and 747 via cables 741 and 743 to connectors 749 and 751on a battery interface board 711. Cable 741 can carry the DC powersignal and cable 743 can carry the data signal. Battery interface board711 can distribute DC power and data to the one or more batteries 352(in FIG. 5, batteries 352 a, 352 b, and 352 c), which can containelectronic circuits that allow them to communicate the respectivecharges so that the controller 150 can monitor and control the chargingand discharging of the one a more batteries 352.

3. Perfusion Fluid Pump

The system 600 can include a pump 106 that is configured to pumpperfusate through the organ care system. The perfusate is typically ablood product-based perfusion fluid that can mimic normal physiologicconditions. In some embodiments, the perfusate can be a synthetic bloodsubstitute solution and/or the perfusate can be a blood product incombination with a blood substitute product. In the embodiments wherethe perfusion fluid is blood-product based, it typically contains redblood cells (e.g., oxygen carrying cells). The perfusate is describedmore fully below.

In some embodiments, the pump 106 can have a systolic phase and adiastolic phase. The amount of perfusate pumped by the pump 106 can bevaried by changing one or more characteristics of the pump itself. Forexample, the number of strokes per minute and/or the stroke displacementcan be changed to achieve the desired flow rate and pressurecharacteristics. In some embodiments, the pump 106 can be configured touse a stroke rate of 1-150 st/min and a displacement of 0.1-1.5″. Morespecifically, however, a nominal stroke rate of 60 st/min±5 st/min canbe used with a displacement of 0.5″. These values are exemplary only andvalues outside of these ranges can also be used. By varying thecharacteristics of the pump 106 flow rates of between 0.0 and 10 L/mincan be achieved.

In some embodiments, a perfusion fluid pump 106 is split into twoseparable portions: a pump driver portion located in the multiple-useportion 650 and a pump interface assembly in the single-use portion 634.This interface assembly of the single-use portion can isolate the pumpdriver of the multiple-use portion from direct blood biologic contact.

FIGS. 6A-6D show an exemplary embodiment of the pump 106. FIGS. 6A-6Cshow various views of a pump interface assembly 300 according to anexemplary embodiment. FIG. 6D shows a perspective view of an exemplarypump-driver portion 107 of the perfusion fluid pump 106. FIG. 6E showsthe pump interface assembly 300 mated with the pump-driver portion 107of the perfusion fluid pump assembly 300, according to one exemplaryembodiment.

The pump interface assembly 300 includes a housing 302 having an outerside 304 and an inner side 306. The interface assembly 300 includes aninlet 308 and an outlet 310. The pump interface assembly 300 can alsoinclude inner 312 and outer 314 O-ring seals, two deformable membranes316 and 318, a doughnut-shaped bracket 320, and half-rings 319 a and 319b that fit between the o-ring 314 and the bracket 320. The half-rings319 a and 319 b can be made of foam, plastic, or other suitablematerial.

The inner O-ring 312 can fit into an annular track along a periphery ofthe inner side 306. The first deformable membrane 316 can mount over theinner O-ring 312 in fluid tight interconnection with the inner side 306of the housing 302 to form a chamber between an interior side of thefirst deformable membrane 316 and the inner side 306 of the housing 302.A second deformable membrane 318 can fit on top of the first deformablemembrane 316 to provide fault tolerance in the event that the firstdeformable membrane 316 rips or tears. Illustratively, the deformablemembranes 316 and 318 can be formed from a thin polyurethane film (about0.002 inches thick). However, any suitable material of any suitablethickness may be employed. Referring to FIGS. 6A and 6B, the bracket 320can mount over the second deformable membrane 318 and the rings 319 aand 319 b and can affix to the housing 302 along a periphery of theinner side 306. Threaded fasteners 322 a-322 i can attach the bracket320 to the housing 302 by way of respective threaded apertures 324 a-324i in the bracket 320. The outer O-ring 314 can interfit into an annulargroove in the bracket 320 for providing fluid tight seal with the pumpassembly 106. Prior to inserting O-ring 314 into the annular groove inbracket 320, the half-rings 319 a and 319 b are typically placed in thegroove. The O-ring 314 can then be compressed and positioned within theannular groove in bracket 320. After being positioned within the annulargroove, the O-ring 314 can expand within the groove to secure itself andthe half-rings 319 a and 319 b in place.

The pump interface assembly 300 can also include heat stake points 321a-321 c, which project from its outer side 304. The points 321 a-321 ccan receive hot glue to heat-stake the pump interface assembly 300 to aC-shaped bracket 656 of the single use portion of the system 300.

As shown in FIG. 6C, the fluid outlet 310 includes an outlet housing 310a, an outlet fitting 310 b, a flow regulator ball 310 c and an outletport 310 d. The ball 310 c is sized to fit within the outlet port 310 dbut not to pass through an inner aperture 326 of the outlet 310. Thefitting 310 b is bonded to the outlet port 310 d (e.g., via epoxy oranother adhesive) to capture the ball 310 c between the inner aperture326 and the fitting 310 b. The outlet housing 310 a is similarly bondedonto the fitting 310 b.

In operation, the pump interface assembly 300 is configured and alignedto receive a pumping force from a pump driver 334 of the perfusion fluidpump assembly 106 and translate the pumping force to the perfusion fluid108, thereby circulating the perfusion fluid 108 to the organ chamberassembly 104. According to the exemplary embodiment, the perfusion fluidpump assembly 106 can include a pulsatile pump having a driver 334,which can contact the membrane 318. The fluid inlet 308 can drawperfusion fluid 108, for example, from the reservoir 160, and providethe fluid into the chamber formed between the inner membrane 316 and theinner side 306 of the housing 302 in response to the pump driver movingin a direction away from the deformable membranes 316 and 318, thusdeforming the membranes 316 and 318 in the same direction.

As the pump driver moves away from the deformable membranes 316 and 318,the pressure head of the fluid 108 inside the reservoir 160 causes theperfusion fluid 108 to flow from the reservoir 160 into the pumpassembly 106. In this respect, the pump assembly 106, the inlet valve191 and the reservoir 160 are oriented to provide a gravity feed ofperfusion fluid 108 into the pump assembly 106. At the same time, theflow regulator ball 310 c is drawn into the aperture 326 to preventperfusion fluid 108 from also being drawn into the chamber through theoutlet 310. It should be noted that the outlet valve 310 and the inletvalve 191 are one way valves in the illustrated embodiment, but inalternative embodiments the valves 310 and/or 191 are two-way valves. Inresponse to the pump driver 334 moving in a direction toward thedeformable membranes 316 and 318, the flow regulator ball 310 c movestoward the fitting 310 b to open the inner aperture 326, which enablesthe outlet 310 to expel perfusion fluid 108 out of the chamber formedbetween the inner side 306 of the housing 302 and the inner side of thedeformable membrane 316. A separate one-way inlet valve 191, shownbetween the reservoir 160 and the inlet 308 in FIG. 1, stops anyperfusion fluid from being expelled out of the inlet 308 and flowingback into the reservoir 160.

In embodiments of the system 600 that are split into the single usemodule 634 and the multiple use module 650, the pump assembly 107 canrigidly mount to the multiple use module 650, and the pump interfaceassembly 300 can rigidly mount to the disposable single use module 634.The pump assembly 106 and the pump interface assembly 300 can havecorresponding interlocking connections, which mate together to form afluid tight seal between the two assemblies 107 and 300.

More particularly, as shown in the perspective view of FIG. 6D, theperfusion fluid pump assembly 107 can include a pump driver housing 338having a top surface 340, and a pump driver 334 housed within a cylinder336 of the housing 338. The pump driver housing 338 can also include adocking port 342, which includes a slot 332 sized and shaped for matingwith a flange 328 projecting from the pump interface assembly 300. Thetop surface 340 of the pump driver housing 338 can mount to a bracket346 on the non-disposable multiple use module 650. The bracket 346 caninclude features 344 a and 344 b for abutting the tapered projections323 a and 323 b, respectively, of the pump interface assembly 300. Thebracket 346 can also include a cutout 330 sized and shaped for aligningwith the docking port 342 and the slot 332 on the pump driver housing338.

Operationally, the seal between the pump interface assembly 300 and thefluid pump assembly 107 can be formed in two steps, illustrated withreference to FIGS. 6D and 6E. In a first step, the flange 328 ispositioned within the docking port 342, while the tapered projections323 a and 323 b are positioned on the clockwise side next tocorresponding features 344 a and 344 b on the bracket 346. In a secondstep, as shown by the arrows 345, 347 and 349, the pump interfaceassembly 300 and the fluid pump assembly 106 are rotated in oppositedirections (e.g., rotating the pump interface assembly 300 in a counterclockwise direction while holding the pump assembly 106 fixed) to slidethe flange 328 into the slot 332 of the docking port 342. At the sametime, the tapered projections 323 a and 323 b slide under the bracketfeatures 344 a and 344 b, respectively, engaging inner surfaces of thebracket features 344 a and 344 b with tapered outer surfaces of thetapered projections 323 a and 323 b to draw the inner side 306 of thepump interface assembly 300 toward the pump driver 334 and to interlockthe flange 328 with the docking ports 342, and the tapered projections323 a and 323 b with the bracket features 344 a and 344 b to form thefluid tight seal between the two assemblies 300 and 106.

In some embodiments, the system 100 can be configured such that the flowcharacteristics including pressure and flow volume of the perfusionfluid provided to the hepatic artery and the portal vein are directlycontrolled and under pressure generated by the pump 106 (e.g., thehepatic artery and portal veins can be in fluid pressure communicationwith the pump 106). This embodiment is different from an embodimentwhere a pump provides perfusion fluid to a reservoir (e.g., a reservoirlocated above the liver) and then uses gravity to provide fluid pressureto the liver.

4. Solution Infusion Pump

The system 600 can include a solution pump 631 that can be configured toinject one or more solutions into the perfusion module circuit. In someembodiments of the organ care system 600, the solution pump 631 can bean off-the-shelf pump such as a MedSystem III from CareFusionCorporation of San Diego, Calif., and/or can be a solution pump asdescribed below with respect to FIGS. 7A-7P. The infusion solutionsprovided by the solution pump 631 can be used to, for example provideongoing management of the organ such as inotropic support, glucosecontrol, pH control. Additionally, while the solution pump 631 isgenerally considered part of the multiple use module 650, parts of thesolution pump 631 can be single use and replaced each time the system isused.

The solution pump 631 can be configured to provide one or more solutionssimultaneously (also referred to has having one or more channels). Insome embodiments, the solution pump 631 can provide three solutions: amaintenance solution, bile salts, and a vasodilator such as epoprostenolsodium. Each of these solutions are described more fully below. Thesolution pump 631 can support multiple infusion rates (e.g., from 1 to200 ml/hr, although higher/lower rates are also possible). The infusionrate can be adjustable in time increments (e.g., 1 ml/hour increment,although higher/lower rates are possible) and changes to the infusionrate typically take effect within five seconds, although this is notrequired. At infusion rates of 10 ml/hr and below, the infused volumecan be accurate to within +/−10% of the infusion rate set point,although this is not required. At infusion rates above 10 ml/hr, theinfused volume can be accurate to within +/−5% of the infusion rate setpoint, although this is not required.

The solution pump can be configured to maintain any required accuracywith input pressures (static pressures relative to the solution pumpline connection) of 0 to −50 mmHg on the solution side and 0 to +220mmHg on the organ side. Preferably, infusions should not have any flowdiscontinuities greater than three seconds. After the solution pump hasbeen de-aired, air bubbles larger than 50 uL are typically not injectedinto the perfusion module. In some embodiments, the portion of the linebetween the solution pump 631 and the organ can include a valve (e.g., apinch valve) to further control the flow of solution to the organ. Thesolution pump 631 can provide status information for each channel suchas infusion state and error.

The solution pump 631 can be used with one or more disposable cartridgesthat provide the solution. For example, the portion of the line betweenthe solution supply and the solution pump 631 can include a spike toconnect to an IV bag. In embodiments that include a disposable cartridgeto supply the solution, the cartridge should be capable of operating forat least 24 hours.

The solution pump 631 can be configured to be controlled via one or morecommunication ports. For example, the solution pump 631 can becontrolled via commands received over via a serial port, a network(e.g., Ethernet, WiFi), and/or cellular communications. Various aspectsof the solution pump 631 can be controlled such as initial availablevolume of solution for each channel, infusion state (e.g., infusing orpaused). A general and/or alarm status for each channel can also beaccessible via the communication port. The status for each channel caninclude an indication of: whether a disposable cartridge is present, aninitial volume is available, an infusing state, an infusing rate, timeremaining until empty, and total volume infused. Additionally, thesolution pump 631 can be configured so that each channel has fault-modeinfusion rate capable of being written/read via the communication port.In some embodiments sensors disposed throughout the organ care system600 can be connected (directly or indirectly through the controller 150)to facilitate automatic control the solution pump 631 by the controller150 using an open or closed feedback loop.

The solution pump 631 can be configured to indicate when failures occur.For example, when a failure or occlusion is detected the solution pump631 can illuminate a fault indicator associated with the faulted channeland/or send a notification via the communication port. The solution pump631 can be configured to pause the infusion in a channel that hasfaulted and can restart the infusion after the fault or occlusion hasbeen cleared. In embodiments where the infusion rates are set via thecommunication port, in the event that signals to/from the communicationport are lost, the solution pump 631 can be configured to set theinfusion rate to a preprogrammed fault-mode infusion rate.

The solution pump 631 can include one or more fault detectionalgorithms/mechanisms. For example, if a hardware failure is detectedthe solution pump 631 can alert a device connected to the communicationport that a hardware fault has occurred. If a solution and/or organ sideocclusion is detected, the solution pump 631 can alert the deviceconnected via communication port that the occlusion has occurred. Thesolution pump 631 can be configured to carry out self tests includingpower on and background self tests. The results of the self tests can beindicated on the solution pump 631 itself and/or communicated via thecommunication port.

As noted above, the solution pump can be an off-the-shelf solution pumpand/or a custom design pump. Referring to FIGS. 7A-7P, an exemplaryembodiment of a custom-designed solution pump 631 is shown anddescribed.

Some embodiments of the solution pump disclosed herein can use a syringeconnected to a motor to control the delivery of an infusion solution. Byincreasing the diameter of the syringe, the capacity of the syringe tohold fluid can be increased. This increased fluid capacity can reducethe number of times the syringe is exchanged for a new, pre-loadedsyringe. However, syringes with an increased diameter can result in theloss of precision during the delivery of solution because as thediameter increases, the amount of solution delivered when the plunger isdepressed one unit also increases. Another exemplary embodiment of thesolution pump uses a relatively small diameter syringe that can allowfor greater precision in the delivery of solution. However, the solutioncan quickly run out due to the syringe's low fluid capacity. Exchangingthe syringe with a new, pre-loaded syringe can create problems such asintroducing air bubbles, interrupting the solution delivery, causing aninconvenience for users, and creating accessibility challenges. Thus, insome embodiments, a relatively small diameter syringe can be connectedto an external source of fluid solution and the perfusion circuit viafluid lines and a series of one-way valves. In these embodiments, as thesyringe is depressed, solution can flow through a one-way valve and intothe perfusion circuit. When the syringe is retracted, the solution canflow through another one-way valve from the external fluid source intothe syringe to refill it with solution. Thus, some embodiments of thisdesign can allow fine precision control of solution delivery (e.g., byusing a smaller diameter syringe) while eliminating the need to replacea preloaded syringe with another.

Referring to FIGS. 7A-7P, an exemplary embodiment of a solution pump9000 is shown. In this embodiment, the solution pump 9000 can use aremovable/replaceable cassette 9020 to provide infusion solutions. FIGS.7C and 7D show an exploded view of the solution pump 9000 and aninfusion cassette 9020, respectively. In this embodiment, the solutionpump 9000 includes three channels, and thus, is configured to provide upto three different solutions. Other embodiments can include more orfewer channels.

The solution pump 9000 can be a syringe pump driven by a stepper motors9002 a, 9002 b, 9002 c. The stepper motors 9002 can rotate respectivelead screws 9005. Carriages 9042 with carriage covers 9004 communicatewith the lead screw 9005 and can move back and forth along the screw9005. The inside of carriages 9042 can also be threaded with matchingthreads to facilitate movement along the lead screw 9005 as the leadscrew 9005 rotates. Additionally, the carriages 9042 can also move alonglinear rails 9041 that facilitate movement back and forth along the leadscrews 9005. Pins 9003 can be attached to the carriage covers 9004 andto a carrier 9036 that is configured to hold a syringe plunger 9017 sothat as the carriages 9042 move back and forth along the lead screws9005, the plunger can be depressed and retracted. The pins 9003 can bethreaded to facilitate attachment to the carrier 9036, although this isnot required. In the embodiment shown in FIGS. 7E, 7F, 7G, 7H, thecarrier 9036 can be shaped to fit around and hold the plunger 9017. Thecarrier 9036 can be manufactured in two pieces that can press fittogether using protrusions 9045, fit together via screws, and/or anyother fastener to clamp the syringe plunger.

In some embodiments, the stepper motor 9002 can be configured to operateat different speeds depending on whether the syringe is being extendedor compressed. For example, when the syringe is being compressed (e.g.during infusion) the motor can move at a low speed such as four stepsper second, whereas when the syringe is being extended (e.g., duringrefill) the motor can be moved at high speed such as 16,000 steps persecond. Other speeds are possible. Additionally, each stepper motor 9002can include an optical encoder on a motor shaft enclosed therein (orelsewhere) that can be used to track the position and/or speed of themotor 9002. Accordingly, the position of the plunger of the syringe canbe calculated.

In the embodiment shown in FIG. 7C, the stepper motors 9002 a, 9002 b,9002 c are positioned in parallel to one another, although otherconfigurations are possible. The pins 9003 pass through slots 9008 in atop cover 9001 and can attach to the carrier 9036 that connects to aplunger 9017 of syringe 9016. The connection between the carriage 9042and the plunger 9017 via the pins 9003 and the carrier 9036 can be usedto depress and retract the syringe, which can cause the syringe toprovide fluid, or refill itself with fluid when properly connected. Forexample, as the stepper motor 9002 rotates the lead screw 9005 in aclockwise manner, the carriage 9042 and the carriage cover 9004 with pin9003 connected to carrier 9036 and plunger 9017 can move in a directionto cause the plunger 9017 to depress and release fluid solution from thesyringe 9016. When stepper motor rotates in a counterclockwise manner,the carriage 9042 can move in an opposite direction and the plunger 9017can be caused to retract, thereby refilling the syringe 9016 with fluidfrom a fluid source, such as an external IV bag.

The solution pump 9000 can include optical switch 9007 that can be usedto detect when the syringe is in a “home” or other position. In someembodiments, the home position can be a position when the syringe isextended and filled with solution, although other home positions arepossible. The optical switch 9007 can be U-shaped and can be configuredto transmit an optical beam between the two upper portions of the U(e.g., by having a transmitter on one side and a receiver on the other).In some embodiments, when the carriage 9042 is in its home position, aflag 9006 on the carriage cover 9004 can interrupt the optical beam fromthe optical switch 9007, thus providing information on the position ofthe syringe. The flag 9006 can be made of any material that interruptsthe optical beam such as opaque plastic and/or metal. In some instancesit can be possible that the solution pump 9000 loses track of theposition of the carriage 9042 because of, for example, a malfunction. Ifthis occurs, the carriage 9042 can return to the home position, leavingthe syringe 9016 filled and the plunger 9017 extended. This can allowthe pump 9000 reattain the position of the syringe without accidentallyproviding any additional solution. In some embodiments of the solutionpump 9000, an additional optical switch 9007 can be included todetermine when the syringe is nearly or completely empty.

The solution pump 9000 can also include pressure sensors 9009 to detectblockages in the delivery line 9010 or output line 9011. An alarm canindicate when the pressure sensors 9009 detect a blockage by sensing apressure over or under predetermined thresholds. The pressure sensor canbe any commercially available sensor suitable for this purpose. In oneembodiment, the sensor can be a MEMSCAP SP854 transducer with hydraulicfluid and a diaphragm. The pressure sensors 9009 can extend through theopenings 9012 in the top cover 9001.

The stepper motor 9002, linear rails 9041, and pressure sensors 9009 canbe mounted to the structural plate 9013. A printed circuit board (“PCB”)9015 can be mounted to the opposite side of the structural plate 9013and include electronics used to operate the solution pump 9000. Theplate 9013 can be made out of aluminum or any other suitable materialand can contain a flange 9014 to provide increased stiffness. The platecan also contain a series of mounting holes to provide a connectionpoint to the top cover and bottom cover.

The top cover 9001 can engage a bottom cover 9018 to enclose thesolution pump 9000. The two parts can engage along the edges and can besecured with screws or another fastener. A mounting plate 9019 canattach to the bottom cover 9018 (labeled as 9015 in some drawings) andto, for example, the inner wall of the system 600. The top cover 9001can also include an opening 9025 for connector cables that can connectelsewhere in the system 600, such as to the controller 150.

The solution pump 9000 can engage an infusion cassette 9020 thatcontains the syringe 9016. In one embodiment the top cover 9001 caninclude a boss 9023 with a pin. As shown in FIGS. 7A, 7B, a tab 9021 onthe infusion cassette 9020 can engage the pin on the boss 9023 toprovide a connection between the solution pump 9000 and the infusioncassette 9020. Additionally, the solution pump 9000 can engage theinfusion cassette 9020 via a circumferential groove on the pressuresensors 9009 that can be received by a pinch release portion 9022 of theinfusion cassette 9020.

The infusion cassette 9020 can include the delivery line 9010 with an IVbag spike 9024 at one end that can be connected to an IV bag or otherexternal source of solution. The other end of the delivery line 9010 canbe connected to a one-way check valve 9026 that is designed to allowfluid to only flow away from the IV bag and toward the syringe 9016. Theone-way check valve 9026 can be connected to a connector 9027. An outputline 9011 can be connected to a second one-way check valve 9032 that isdesigned to allow fluid to only flow away from the syringe 9016 andtowards a port 9034. The one-way check valve 9032 can also be connectedto the connector 9027. The output line 9011 can include a filter 9033that filters particulate and air from the solution. The filter 9033 canbe any filter with hydrophobic properties that are suitable for thispurpose. The output line 9011 can also be coupled to the port 9034 thatconnects to the perfusion module. Port 9034 can include a luer fitting.The output line 9011 can also include a roller clamp 9035 that can closethe output line 9011. During use, the roller clamp 9035 can be kept opento allow fluid to pass through the output line 9011.

Referring to FIGS. 7I-7K, the connector 9027 can be, for example, aY-connector. The connector 9027 can include connectors 9043, 9044.Connector 9043 can be connected to the delivery line 9010 and connector9044 can be connected to the output line 9011. Connector 9027 can alsoinclude vertical infusion line. The vertical infusion line can connectto a connector mount. The connector 9027 can also include an alignmenttab 9028.

Referring to FIGS. 7L-7P, an exemplary connector mount 9029 is shown.Connector mount 9029 can include a connection port 9031 that can becoupled to the connector 9027 and a syringe mount 9030 that can becoupled to the syringe 9016. A pressure membrane (not shown) can beplaced in the connector mount 9029 to monitor the pressure in the fluidcircuit between the syringe 9016, the delivery line 9010, and the outputline 9011 (e.g., using the pressure sensor 9009). The pressure membranecan be attached to the connector mount 9029 at a location opposite theconnection port 9031. The connector mount 9029 can also be used toremovably attach the cassette 9020 to the top cover 9001 using a snapconnector. For example, wings 9055 can extend through openings in thetop cover 9037. By squeezing the wings 9055 together a bottom portion9056 can be flexed outwards releasing it from a corresponding connectorportion on, for example, the pressure sensor 9009.

In one embodiment, the syringe 9016 can deliver fluid as the plunger9017 is compressed by the movement of the carriage 9042 along the leadscrew 9005 by the stepper motor 9002. The fluid from the syringe canpass into the vertical infusion line, past the one-way check valve 9032,into the output line 9011, through the filter 9033, and into theperfusion fluid being circulated in the system 600. Once the plunger9017 is nearly or fully compressed so that there is little or no fluidto deliver from the syringe, the syringe can be retracted, allowingfluid to pass from the IV bag (not shown), through delivery line 9010,past the one-way check valve 9026, into the vertical infusion line, andinto the syringe 9016, thus refilling the syringe.

The infusion cassette can include a top cover 9037 that can engage abottom cover 9038, thus enclosing the syringe 9016. A gasket 9039 canprovide a seal around slots 9008 in top cover 9001 to keep fluid fromentering the solution pump 9000 through the slots 9008. The gasket canbe made of any suitable sealing material, including foam. A shippinglock 9040 can retain the plunger 9017 and carrier in the fully retractedposition so that carriage 9042 can be engaged in the home position. Onepurpose of the shipping lock 9040 can be to ensure that the hole 9092 incarrier 9036 is at the correct location so that the drive pin 9003protrudes into the hole 9092 when the user installs the cassette 9020.The shipping lock 9040 can be removed before use.

As will be appreciated, the type and configuration of syringe used inthe cassette 9020 can affect how the system is controlled. For example,as the bore of the syringe increases, less travel of the plunger isneeded to provide a given amount of solution. Additionally, syringes canhave different capacities which can affect how often the syringe needsto be refilled. Thus, it can be beneficial for the solution pump 9000 toknow what kind of syringe is installed in cassette 9020. Accordingly, insome embodiments the system 9000 includes a mechanism by which it candetermine what type of syringe is included in the cassette 9020. Forexample, in an embodiment of the solution pump 9000 is configured towork with two different types of syringes, the pump can include a magnetand Hall effect sensor that can be configured to determine which of thetwo types of syringes is being used. For example, the cassette 9020 caninclude a magnet having N and S poles. The magnet can be oriented sothat only one of the two poles interacts with the Hall effect sensor.When the first type of syringe is used, the N pole can be configured tointeract with the Hall effect sensor and, likewise, when the second typeof syringe is used, the S pole can be configured to interact with theHall effect sensor. By determining which of the two poles is interactingwith the Hall effect sensor, the solution pump 9000 can determine whichtype of syringe is being used in the cassette 9020. The sensorconfiguration is exemplary only, and other sensors can be used todetermine which type of syringes being used in the cassette 9020.

The solution pump 9000 can be controlled by one or more control systems.For example, the solution pump 9000 can be controlled by the controller150 and/or can include an internal control system. Regardless of thelocation of the controller, the controller can be configured to know howmany partial or full rotations of the stepper motor 9002 are required toprovide the necessary amount of solution and/or to refill the syringe.Thus, for example, the controller can know that it takes 40 steps of thestepper motor to provide 1 mL of solution. In some embodiments, theamount of solution provided by the solution pump 9000 can be manuallycontrolled and/or can be controlled automatically by the controller 150.

The solution pump 631 can be configured to provide solution flow ratesthat vary between 0.5 and 200 mL/hr, although other rates are possible.

Some embodiments of the solution pump 631 can include a priming cyclethat can be used to prime and eliminate air within the lines of the pump631. For example, a user can assemble a complete line set dry andperform priming cycle until air is eliminated. For example, each primingcycle can advance 3 mL of air (or solution) using a special fast-forwardand fast refill movement. In some embodiments, the prime cycle is underuser control and/or can be performed automatically.

In some embodiments, when the motor 9002 is operated at a high speed(e.g., during refill and/or priming), the high-speed cycle can include aramp-up and ramp down periods going into and coming out of high-speedoperation. These ramp-up and ramp down periods can be used to overcomethe rotational inertia of the motor 9002. This function can beimplemented by the firmware and/or controller is controlling the pump631 using, for example lookup tables that have been calculated to adjustthe pulse rates of the motors 9002 for constant acceleration and/ordeceleration. The ramp-up and ramp down periods can also be used duringlow-speed operation.

In some embodiments, the solution pump 631 can be configured tocompensate for inherent backlash that can be caused when the directionof travel of the syringe is reversed. For example, fluid flow can beparticularly affected by the backlash inherent in the motor 9002 andlead screw 9005. Errors caused by backlash can affect the resumption ofinfusion flow after a refill cycle. To offset these possible errors,firmware within the pump and/or the controller can capture the pressurein the syringe chamber at the end of all infusion strokes. The fastrefill cycle can then be executed and the firmware and/or controller canadvance the plunger at a moderately fast rate until the pressure in thesyringe chamber is equal to the pressure captured during the lastinfusion strokes. When that pressure is reached, all system backlash hastypically been resolved and the pump can continue infusing at thedesired rate.

While stepper motors typically provide the highest torque for a givenmotor size, and can be easy to drive, they can also consume high amountsof power and can generate large amounts of mechanical noise. Thus, insome embodiments of the pump 631, firmware and/or the controller caninclude a dynamic torque function that can operate the motors 9002 atthe minimal torque required at any given time. This can be accomplishedusing digital to analog converters that control the current limit ofeach stepper motor driver, which can in turn control the torque providedby the motor. Accordingly, stepper motor torque can be adjusted toefficiently provide the required motion. At rest, a small current can beprovided to the motor to maintain its static position without slipping.At the start of each forward infusion stroke, the stepper motor can berun at the selected infusion rate with a predefined minimal torque. Ifthe encoder indicates that the stepper is not moving as desired, thetorque can be increased until the proper movement is achieved. In thisway, the forward infusion stroke can be performed at the minimal torquerequired to do the job.

The solution pump 631 can also be configured to make up for slippagebetween the actual position and the desired position of the syringeplunger. For example, when firmware and/or the controller determinesthat the syringe position (e.g. provided by an encoder) has slippedbehind the desired profile, it can double the rate until the syringeposition catches up. This process of slipping, torque increase, and/orrate doubling can happen quickly enough to provide uninterruptedinfusion at the selected rate.

FIG. 7Q shows an exemplary embodiment of a microcontroller architecturethat can be included in the solution pump 631, although this is notrequired and other configurations are possible. In this embodiment, themicrocontroller architecture includes a processor (e.g. PIC 18F8722processor) that receives inputs from, for example, the controller 150,pressure input sensors, motor current and diagnostic voltage sensors,Hall magnetic sensors, photo interrupters, and/or encoder inputs. Usingthe information it receives, the processor can provide feedback to thecontroller 150 and/or can control the stepper motor drive to actuate thesyringes in the respective channels.

5. Gas System, Including Variable Delivery Rate Control

The multiple use module 650 can include an on-board gas supply such asone or more common gas cylinders that can fit into the gas tank bay 630and/or an oxygen concentrator. The gas supply system can include: i) oneor more regulators to reduce the pressure of the gas provided by one ormore gas cylinders, ii) pressure sensors that are configured to measurethe pressure in the gas supply, and ii) gas pressure gauge that canprovide a visual indication of the fullness of the gas supply. Each ofthese components can be manually controlled and/or can be connected andautomatically controlled by the controller 150. For example, thecontroller 150 can automatically regulate the gas flow into the gasexchanger 114. While the gas provided by the gas provided by the gassource can vary, in some embodiments, the gas supply can provide a gascomprised of 85% O₂, 1% CO₂, and the balance N₂ with a blend processaccuracy of 0.030%, while in some embodiments the gas supply can bebetween 50% O₂ and 95% O₂ and the balance N₂ and/or Ar. In someembodiments the multiple gasses can be supplied premixed from a singlecylinder or can be provided from multiple gas cylinders and mixed withinthe system 600. In some embodiments gas can be supplied from a portableoxygen concentrator, such as the Oxus Portable Oxygen Concentrator fromOxus, Inc. of Rochester Hills, Mich., or a Freestyle series portableoxygen concentrator available from AirSep, or Buffalo, N.Y.

In some embodiments the system 600 can support a gas flow rate of 0-1000mL/min and can have a set point resolution of 50 ml/min with a gas flowdelivery accuracy of ±20% in the range from 200-1000 mL/min. The system600 and the gas supply 172 can be configured to provide a gas flow inthe event of a circulatory pump fault. The ranges listed above areexemplary, and values outside of those specifically identified can alsobe used. Lastly, in some embodiments the system 600 and the gas supply172 can be configured to provide an indicator of the pressure in the gassupply 172 via multiple interfaces (e.g., via a gauge on the gas supply172 and/or the operator interface module 146).

6. Controller and User Interface

The system 600 can include a control system (e.g., controller 150) thatcontrols the overall operation of the system 600 and the components usedtherein. At a general level, the control system can include an onboardcomputer system that is connected to one or more of the components inthe system 600 and to one or more sensors, network connections, and/oruser inputs. Using the information obtained from the sensors, networkconnections, and/or user inputs, the control system can control thevarious components in the system 600. For example, the control systemcan be used to implement one or more open or closed feedback systems tocontrol operation of the system 600. The control system can be a commonoff-the-shelf computer and/or a specially designed computer system. Itshould be noted that although the system 600 is described conceptuallywith reference to a single controller, the control of the system 600 canbe distributed in a plurality of controllers or processors. For example,any or all of the described subsystems may include a dedicatedprocessor/controller. Optionally, the dedicated processors/controllersof the various subsystems may communicate with and via a centralcontroller/processor. For example, in some embodiments, a singlecontroller located in the multiple-use module 650 can control the entiresystem 600, in other embodiments a single controller located in thesingle-use module 634 can control the entire system 600, and in stillother embodiments, the controller can be split between the single-usemodule 634 and the multiple-use module 650.

As a further example, in some embodiments, the controller 150 can belocated on the main circuit board 718 and can perform all control andprocessing required by the system 600. However, in other embodiments,the controller 150 can distributed, locating some processingfunctionality on the front end interface circuit board 636, some on thepower circuit board 720, and/or some in the operator interface module146. Suitable cabling can be provided between the various circuitboards, depending on whether and the degree to which the controller 150is distributed within the system 600.

FIG. 8 depicts an exemplary block diagram of an illustrative controlscheme for the system 600. For example, the system 600 can include acontroller 150 for controlling operation of the system 600. As shown,the controller 150 can connect interoperationally several subsystems: anoperator interface 146 that can assist an operator in monitoring andcontrolling the system 600 and in monitoring the condition of the organ;a data acquisition subsystem 147 that can include various sensors forobtaining data relating to the organ and to the system 600, and forconveying the data to the controller 150; a power management subsystem148 for providing fault tolerant power to the system 600; a heatingsubsystem 149 for providing controlled energy to the heater 110 forwarming the perfusion fluid 108; a data management subsystem 151 forstoring and maintaining data relating to operation of the system 600 andwith respect to the liver; and a pumping subsystem 153 for controllingthe pumping of the perfusion fluid 108 through the system 600.

An exemplary embodiment of the data acquisition subsystem 147 will nowbe described with reference to FIG. 9. In this embodiment, the dataacquisition subsystem 147 include sensors for obtaining informationpertaining to how the system 600 and the liver is functioning. The dataacquisition subsystem 147 can provide this information to the controller150 for processing. For example, the data acquisition subsystem 147 canbe coupled to the following sensors: temperature sensors 120, 122, 124;pressure sensors 126, 128, 130 (which can be the pressure sensors 130 a,130 b referred to elsewhere herein); flow rate sensors 134, 136, 138;the oxygenation/hematocrit/temperature sensor 140; Hall sensors 388;shaft encoder 390; battery sensors 362 a, 362 b, 362 c; external poweravailable sensor 354; and operator interface module battery sensor 370;a gas pressure sensor 132. How the system 600 uses the information fromthe data acquisition subsystem 147 will now be described with regard tothe heating 149, power management 148, pumping 153, data management 151,and operator interface 146 subsystems.

Referring to FIG. 10, this figure depicts an exemplary block diagram ofthe power management system 148 for providing fault tolerant power tothe system 600. The system 600 can be powered by one of multiple sourcessuch as an external power source (e.g., 60 Hz, 120 VAC in North Americaor 50 Hz, 230 VAC in Europe) or by any of the one or more batteries 352.While the remainder of this description refers to an AC power source asthe external power source, it is to be understood that a DC power sourcecan also be used. The controller 150 can receive data from an AC linevoltage availability sensor 354, which can indicate whether the ACvoltage 351 is available and/or sufficient for use by the system 600.

In response to the controller 150 detecting that external power is notavailable, the controller 150 can signal the power switching circuitry356 to provide system power from the one or more batteries 352. Thecontroller 150 can determine from the battery charge sensors 362 whichof the one or more batteries 352 is most fully charged, and can thenswitch that battery into operation by way of the switching network 356.The system can be designed to prevent interruptions in the operation ofthe system 600 as the power is switched from one source to another.

Alternatively, in response to the controller 150 detecting that suitableexternal power is available, the controller 150 can determine whether touse the external power for providing system power and for providingpower to the user interface module 146, for charging the one or morebatteries 352, and/or for charging the internal battery of userinterface module 146, which can also have its own internal charger andcharging controller. To use available external power (e.g., AC power141) the controller 150 can draw the external power into the powermanagement system 148 by signaling through the switching system 164. Inthe event that the external power source is AC, the power managementsystem 148 can also receive the external AC and convert it to a DC forproviding power to the system 600. The power management system 148 canbe universal and can handle any line frequencies or line voltagescommonly used throughout the world. According to the illustrativeembodiment, in response to a low battery indication from one or more ofthe battery sensors 362, the controller 150 can also direct power viathe switching network 364 and the charging circuit 366 to theappropriate battery. In response to the controller 150 receiving a lowbattery signal from the sensor 370 (which can monitor a battery in theuser interface module 146), it can also or alternatively direct acharging voltage 367 to the user interface battery 368. In someembodiments, the power management subsystem 148 can select batteries topower the system 600 using an algorithm to best provide for batterylongevity, including selecting in order of least-charged first as wellas other factors, such as least number of charge cycles. If the batterythat is currently being used to power the system 600 is removed by theuser, the power management subsystem 148 can automatically switch to thenext battery per the algorithm to continue powering the system 600.

Referring to FIG. 11, an exemplary embodiment of the heating subsystem149 is shown. The heating subsystem 149 can control the temperature ofthe perfusion fluid 108 within the system 600 through, for example, adual feedback loop approach. In the first loop 251 (the perfusion fluidtemperature loop), the perfusion fluid temperature thermistor sensor 124provides two (fault tolerant) signals 125 and 127 to the controller 150.The signals 125 and 127 are typically indicative of the temperature ofthe perfusion fluid 108 as it exits the heater assembly 110. Thecontroller 150 can regulate the drive signals 285 and 287 to the drivers247 and 249, respectively. The drivers 247 and 249 can convertcorresponding digital level signals 285 and 287 from the controller 150to heater drive signals 281 and 283, respectively, having sufficientcurrent levels to drive the first 246 and second 248 heaters to heat theperfusion fluid 108 to within a desired temperature range. In responseto the controller 150 detecting that the perfusion fluid temperatures125 and 127 are below the desired temperature range, it can set thedrive signals 281 and 283 to the first 246 and second 248 heaters,respectively, to a sufficient level to continue to heat the perfusionfluid 108. Conversely, in response to the controller 150 detecting thatthe perfusion fluid temperatures 125 and 127 are above the desiredtemperature range, it can decrease the drive signals 281 and 283 to thefirst 246 and second 248 heaters, respectively. In response to detectingthat the temperature of the perfusion fluid 108 is within the desiredtemperature range, the controller 150 can maintain the drive signals 281and 283 at constant or substantially constant levels. The temperaturecontrol system can be controlled to warm the perfusate to a temperaturerange between 0-50° C., and more specifically between 32-42° C., andeven more specifically between 32-37° C. These ranges are exemplary onlyand the temperature control system can be controlled to warm theperfusate to any temperature range falling within 0-50° C. The desiredtemperature can be user-selectable and/or automatically controlled bythe controller 150. As used herein and in the claims, “normothermic” isdefined a temperature between 34-37° C.

In some embodiments, the controller 150 can vary the drive signals 281and 283, which can control the first and second heaters, insubstantially the same manner. However, this is not required. Forexample, each heater 246 and 248 may respond differently to a particularcurrent or voltage level drive signal. In such a case, the controller150 can drive each heater 246 and 248 at a slightly different level toobtain the same temperature from each. In some embodiments, the heaters246 and 248 can each have an associated calibration factor, which thecontroller 150 stores and employs when determining the level of aparticular drive signal to provide to a particular heater to achieve aparticular temperature result. In certain configurations, the controller150 can set one of the thermistors in dual sensor 124 as the defaultthermistor, and will use the temperature reading from the defaultthermistor in instances where the thermistors give two differenttemperature readings. In some embodiments, where the temperaturereadings are within a pre-defined range, the controller 150 can use thehigher of the two readings. The drivers 247 and 249 can apply the heaterdrive signals 281 and 283 to corresponding drive leads 282 a and 282 bon the heater assembly 110.

In the second loop 253 (the heater temperature loop), the heatertemperature sensors 120 and 122 can provide signals 121 and 123,indicative of the temperatures of the heaters 246 and 248, respectively,to the controller 150. According to the illustrated embodiment, atemperature ceiling can be established for the heaters 246 and 248(e.g., by default, operator selection, or automatically determined bythe controller 150), above which the temperatures of the heaters 246 and248 are not allowed to rise. As the temperatures of the heaters 246 and248 rise and approach the temperature ceiling, the sensors 121 and 123can indicate the same to the controller 150, which can then lower thedrive signals 281 and 283 to the heaters 246 and 248 to reduce or stopthe supply of power to the heaters 246 and 248. Thus, while a lowtemperature signal 125 or 127 from the perfusion fluid temperaturesensor 124 can cause the controller 150 to increase power to the heaters246 and 248, the heater temperature sensors 120 and 122 ensure that theheaters 246 and 248 are not driven to a degree that would cause theirrespective heater plates 250 and 252 to become hot enough to damage theperfusion fluid 108.

In some embodiments, the controller 150 can be configured to maintainthe perfusion fluid temperature between 0-50° C. In some embodiments theperfusate is maintained within a temperature range of 32-42° C., or insome more specific embodiments in the rage of 35-37° C. In someembodiments, the controller can be configured to limit the temperatureof the heater plates 250 and 252 to 38° C., 39° C., 40° C., 41° C., or42° C. All of the ranges and numbers identified herein are exemplary andvalues outside of these ranges can also be used. Lastly, to the extentthat the claims recite “substantially” in connection with a specifictemperature value or range, this means that the temperature is to bewithin the operational temperature swing range of the heater/controlsystem used. For example, if the claimed temperature is “substantially32° C.,” and a heater/control system is used in an accused product thatmaintains the temperature within ±5% of a desired value, then anytemperature that is ±5% of 32° C. is “substantially 32° C.”

As can be seen, the second loop 253 can be configured to override thefirst loop 251, if necessary, such that temperature readings fromtemperature sensors 120 and 122 indicating that the heaters 246 and 248are approaching the maximum allowable temperature override the effect ofany low temperature signal from the perfusion fluid temperature sensor124. In this respect, the subsystem 149 can ensure that the temperatureof the heater plates 250 and 252 do not rise above the maximum allowabletemperature, even if the temperature of the-perfusion fluid 108 has notreached the desired temperature value. This override feature can beparticularly important during failure situations. For example, if theperfusion fluid temperature sensors 124 both fail, the second loop 253can stop the heater assembly 110 from overheating and damaging theperfusion fluid 108 by switching control exclusively to the heatertemperature sensors 120 and 122 and dropping the temperature set pointto a fixed value. In some embodiments, the controller 150 can take intoaccount two time constants assigned to the delays associated with thetemperature measurements from the heaters 246 and 248 and perfusionfluid 108 to optimize the dynamic response of the temperature controls.

In some embodiments, the user can be provided with the option to disablethe blood warming feature of the system 600. In this manner, the systemcan more efficiently support cooling of the liver during thepost-preservation chilling procedure. In some embodiments, the heaterassembly 110 (or a separate device, such as a gas exchanger withintegrated cooling interface) can function as a chiller to cool thetemperature of the perfusion fluid.

Turning now to the operator interface subsystem 146, FIGS. 12A-12G showvarious exemplary display screens of the operator interface subsystem146. The display screens can enable the operator to receive informationfrom and provide commands to the system 600. FIG. 12A depicts anexemplary top level “home page” screen 400. From the screen 400 anoperator can typically access most if not all of the data available fromthe data acquisition subsystem 147, and can typically provide anydesired commands to the controller 150. For example, a user can monitorand adjust the pumping subsystem 153 via the screen 400. As described inmore detail in reference to FIGS. 12B-12G, the screen 400 can also allowthe operator to access more detailed display screens for obtaininginformation, providing commands and setting operator selectableparameters.

In this exemplary embodiment, the screen 400 includes various portionseach displaying different pieces of information and/or acceptingdifferent inputs. However, screen 400 is exemplary only and theinformation displayed by the screen 400 can be customized by the user(e.g., using dialog 590 described below in FIG. 12F). The valuesdisplayed on the screen 400 can be updated at regular intervals such asonce every second. In this particular example, the screen 400 includesthe following portions:

-   -   Portion 402 that displays the hepatic artery flow rate. This        value can be an indication of the flow at the flow sensor 138 b.    -   Portion 404 that displays the portal vein flow rate. This value        can be an indication of the flow at the flow sensor 138 a.    -   Portion 406 that displays the oxygen saturation (SvO₂) of the        perfusion fluid leaving the liver as measured by, for example,        the sensor 140.    -   Portion 408 that displays the hematocrit (HCT) level of the        perfusion fluid leaving the liver as measured by, for example,        the sensor 140.    -   Portion 410 that displays the desired and measured temperature        of the perfusate. In this embodiment, the larger, top number        represents the measured temperature whereas the smaller number        listed below represents the temperature at which the desired        perfusate temperature is set. The temperature can be measured        from one of more locations such as at the output of the heater        assembly 110 using the temperature sensors 120 and 122, and in        some embodiments sensor 140.    -   Portion 412 that displays the flow rate as measured by flow        sensor 136.    -   Portion 414 that displays systolic/diastolic pressure in the        hepatic artery. The number in parentheses below the        systolic/diastolic pressures is an arithmetic mean of the        pressure waveform. This systolic/diastolic/mean pressure in the        hepatic artery can be determined by the pressure sensor 130 a.    -   Portion 416 that displays a waveform of the hepatic artery        pressure over time.    -   Portion 418 that displays systolic/diastolic pressure in the        portal vein. Number in parentheses below the systolic/diastolic        pressures is an arithmetic mean of the two. The        systolic/diastolic pressure in the portal vein can be determined        by the pressure sensor 130 b.    -   Portion 420 that displays a waveform of the portal vein pressure        over time.    -   Portion 422 that displays the hepatic artery pressure averaged        over time (e.g., two minutes).    -   Portion 424 that displays the hepatic artery flow rate averaged        over time (e.g., two minutes).    -   Portion 426 that a graphical representation of the values from        portion 422 and 424 over time. In this embodiment, the graph        represents a 3½ hour time window. In some embodiments, the        portion 426 can be controlled by the user to show different        periods of time.    -   Portion 428 that displays an icon showing that the perfusion        pump is running.    -   Portion 429 (which is not illuminated in this example) can show        an organ type indicator that indicates which organ is being        perfused and which mode of operation is being used. For example,        an “M” can be used to indicate that the system 600 is in a        maintenance mode.    -   Portion 430 that displays the status of a storage medium        included in the system 600 (e.g., an SD card).    -   Portion 432 that displays the flow rate from the onboard gas        supply. This portion can also display the amount of time        remaining before the onboard gas supply runs out.    -   Portion 434 that displays the status of the power supply system.        In this embodiment, the system 600 includes three batteries,        where each battery has a corresponding status indicator showing        the degree to which the battery is charged. This portion also        indicates whether the system 600 is connected to an external        power source (by showing a plug icon). In some embodiments, this        portion can also include a numerical indication of the amount of        time that the batteries can run the system 600 in the current        mode of operation.    -   Portion 436 that displays the status and charge remaining of the        battery included in the operator interface module 146. This        portion can also include an indication of the amount of time        remaining for which the battery in the operator interface module        146 can support it in a wireless mode of operation.    -   Portion 438 that displays the status of a network and/or        cellular connection. This portion can also identify whether the        operator interface module 146 is operating in a wireless 464        fashion, along with a graphical representation 463 of the        strength of the wireless connection between the operator        interface module 146 and the remainder of the system 600.

Additional portions can be displayed to show when one or more alarmsand/or portions of the system 600 have been disabled by the user.

As can be seen in FIG. 12A-12G some portions can also include alarmrange indicators (e.g., indicator 440) that indicates where the currentvalue falls within an allowable range. Each portion can also include analarm indicator (not shown) indicating that the respective values areoutside of the range indicated by the corresponding range indicator. Therange indicator for each respective value can be tied to the alarmvalues set in dialog 512 or independently set by the user. The screen400 can be implemented on a touch screen interface. In portions thataccept user input, the user can touch a specific portion to change thevalue therein using the knob 626.

Referring to FIGS. 12B, 12C, and 12D, a user can select to enter aconfiguration menu 484. In some embodiments of the system, theconfiguration menu 484 can be limited to a portion of the screen so thatthe user can continue to monitor the information displayed on thescreen. Using the configuration menu, the user can program desiredoperational parameters for the system 600. In this embodiment of theconfiguration menu 484, the menu has three tabbed pages 484 a, 484 b,484 c (“Liver,” “System,” and “Actions”).

In tabbed page 484 a, the Liver tab is shown. In this tab the user isable to enter alarm dialog 512 (described below with respect to FIG.12E), select the data shown in the middle graphic frame, select the datashown in the bottom graphic frame, set the desired gas flow rate, andset the desired temperature. Changes made in the tabbed page 484 a canbe reflected in the screen 400.

In tabbed page 484 b, the System tab is shown. In this tab, the user canadjust one or more display features of the system 600. For example, theuser can select which units are used to display the various measurements(e.g., pascal versus mmHg), can restore factory defaults, can store newdefault settings, and can restore saved default settings. From this taba service technician can also enable a wireless connection from aservice laptop to the system 600. Changes made in the tabbed page 484 bcan be reflected in the screen 400.

In tabbed page 484 c, the Actions tab is shown. In this menu, the usercan display the status of the machine, display a summary of all of thealarms, can adjust the scale of displayed measurements, and/or caninteract with the data stored by the system 600. For example, in someembodiments the user can withdraw a sample of the perfusion fluid andperform an external test on it. The user can then manually enter thevalue obtained by the external test into the data stream beingmaintained by the system 600. In this manner, system 600 can include alldata relevant to the organ being transplanted, regardless of whetherthat data was generated externally from the system 600.

Referring to FIG. 12E, alarm dialog 512 displays the parametersassociated with the operation of the system 600. In this embodiment,there are alarms for hepatic artery flow (HAF), portal vein pressure(PVP), hepatic artery pressure (HAP), inferior vena cava pressure(IVCP), perfusion fluid temperature (Temp), oxygen saturation (SvO₂),hematocrit (HCT). More of fewer parameters can be included in the dialog512. Row 514 indicates an upper alarm limit (e.g., a value above thisnumber will cause an alarm) and row 516 indicates a lower alarm limit(e.g., a value below this number will cause an alarm). The user can alsoenable/disable individual alarms by selecting the associated alarm iconin row 518. The icons in row 518 can indicate whether an individualalarm is enabled or disabled (e.g., in FIG. 12E the alarm for IVCP isdisabled). The alarm limits can be predetermined, user settable, and/ordetermined in real-time by the controller 150. In some embodiments, thesystem 600 can be configured to automatically switch between sets ofalarm limits for a given flow mode upon changing the flow mode. Changesmade in the dialog 512 can be reflected in the screen 400.

FIG. 12F shows an exemplary user interface (dialog 590) in which a usercan select what the various portions of screen 400 display. For example,in FIG. 12F, the user can choose to display the realtime waveform of thehepatic artery pressure, portal vein pressure or IVC pressure, or chooseto display trend graphs for those or other measured parameters in aportion of the screen 400. Other waveforms can also be calculated anddisplayed by the controller 150.

FIG. 12 G shows an exemplary user interface (dialog 592) in which a usercan adjust parameters of the pumping subsystem 153. In this example, theuser can adjust the pump flow and turn the pump on/off.

The data management subsystem 151 can receive and store data and systeminformation from the various other subsystems. The data and otherinformation can be downloaded to a portable memory device and organizedwithin a database, as desired by an operator. The stored data andinformation can be accessed by an operator and displayed through theoperator interface subsystem 146. The data management system 151 can beconfigured to store in the information in one or more places. Forexample, the data management subsystem 151 can be configured to storedata in storage that is internal to the system 600 (e.g., a hard drive,a flash drive, an SD card, a compact flash card, RAM, ROM, CD, DVD)and/or external to the system (e.g., a remote storage memory or Cloudstorage).

In embodiments using external storage, the data management subsystem 151(or another part of the controller 150) can communicate with theexternal storage over various communication connections such aspoint-to-point network connections, intranets, and the Internet. Forexample, the data management subsystem 151 can communicate with a remotestorage medium or “the Cloud” (e.g., data servers and storage devices ona shared and/or private network) via a WiFi network (e.g., 802.11), acellular connection (e.g., LTE), a Bluetooth (e.g., 802.15), infraredconnection, a satellite-based connection, and/or a hard-wired networkconnection (e.g., Ethernet). In some embodiments, the data managementsubsystem can be configured to automatically detect the best networkconnection to communicate with the remote storage device and/or Cloud.For example, the data management subsystem can be configured to defaultto known WiFi networks and automatically switch to a cellular networkwhen no known WiFi networks are available. Remote and Cloud basedembodiments are discussed more fully below.

Referring to FIG. 12H, the pumping subsystem 153 will now be describedin further detail. The controller 150 can operate the pumping subsystem153 by sending a drive signal 339 to a brushless three-phase pump motor360 using Hall Sensor feedback. The drive signal 339 can cause the pumpmotor shaft 337 to rotate, thereby causing the pump screw 341 to extentand retract the pump driver 334. According to the illustrativeembodiment, the drive signal 339 is controlled to change a rotationaldirection and rotational velocity of the motor shaft 337 to cause thepump driver 334 to extract and retract cyclically. This cyclical motioncan pump the perfusion fluid through the system 600.

The controller 150 can receive a first signal 387 from the Hall sensors388 positioned integrally within the pump motor shaft 337 to indicatethe position of the pump motor shaft 337 for purposes of commutating themotor winding currents. The controller 150 can receive a second higherresolution signal 389 from a shaft encoder sensor 390 indicating aprecise rotational position of the pump screw 341. From the currentmotor commutation phase position 387 and the current rotational position389, the controller 150 can calculate the appropriate drive signal 339(both magnitude and polarity) to cause the necessary rotational changein the motor shaft 337 to cause the appropriate position change in thepump screw 341 to achieve the desired pumping action. By varying themagnitude of the drive signal 339, the controller 150 can vary thepumping rate (i.e., how often the pumping cycle repeats) and by varyingthe rotational direction changes, the controller 150 can vary thepumping stroke volume (e.g., by varying how far the pump driver 334moves during a cycle). Generally speaking, the cyclical pumping rateregulates the pulsatile rate at which the perfusion fluid 108 isprovided to the liver, while (for a given rate) the pumping strokeregulates the volume of perfusion fluid provided to the liver.

Both the rate and stroke volume affect the flow rate, and indirectly thepressure, of the perfusion fluid 108 to the liver. As described herein,the system 600 can include three flow rate sensors 134, 136 and 138, andthree pressure sensors 126, 128, and 130. The sensors 134, 136, and 138can provide corresponding flow rate signals 135, 137 and 139 to thecontroller 150. Similarly, the sensors 126, 128 and 130 can providecorresponding pressure signals 129, 131 and 133 to the controller 150.The controller 150 can use all of these signals in feedback to ensurethat the commands that it is providing to the perfusion pump 106 havethe desired effect on the system 600. In some instances, the controller150 can generate various alarms in response to a signal indicating thata particular flow rate or fluid pressure is outside an acceptable range.Additionally, employing multiple sensors enables the controller 150 todistinguish between a mechanical issue (e.g., a conduit blockage) withthe system 600 and a biological issue with the liver.

While the above discloses the use of three pressure sensors, this is notrequired. In many of the embodiments described herein only two pressuresensors are used (e.g., pressure sensors 130 a, 130 b). In thisinstance, the input for the third pressure sensor can be ignored.However, in some embodiments of the system disclosed herein a thirdpressure sensor can be used to measure the pressure in the perfusionfluid flowing from the inferior vena cava (or elsewhere in the system100). In this instance, the controller 150 can process the pressuresignal from the sensor as described above.

The pumping system 153 can be configured to control the position of thepump driver 334 during each moment of the pumping cycle to allow forfinely tuned pumping rate and volumetric profiles. This can enable thepumping system 153 to supply perfusion fluid 108 to the liver with anydesired pulsatile pattern. According to one illustrative embodiment, therotational position of the shaft 337 can be sensed by the shaft encoder390 and adjusted by the controller 150 at least about 100 increments perrevolution. In another illustrative embodiment, the rotational positionof the shaft 337 is sensed by the shaft encoder 390 and adjusted by thecontroller 150 at least about 1000 increments per revolution. Accordingto a further illustrative embodiment, the rotational position of theshaft 337 is sensed by the shaft encoder 390 and adjusted by thecontroller 150 at least about 2000 increments per revolution. Theposition of the pump screw 341 and thus the pump driver 334 can becalibrated initially to a reference position of the pump screw 341.

As described above, the system 600 can be manually controlled using thecontroller 150. However, some or all of the control of the system can beautomated and performed by the controller 150. For example, thecontroller 150 can be configured to automatically control the pump 106flow of the perfusion fluid (e.g., pressure flow rate), the solutionpump 631, the pump 106, the gas exchanger 114, the heater 110, and/orthe flow clamp 190. Control of the system 600 can be accomplished usingminimal, or even no intervention by the user. For example, thecontroller 150 can be programmed with one or more predetermined routinesand/or can use information from the various sensors in the system 600 toimplement open and/or closed feedback loops. For example, if thecontroller determines that the oxygenation level of the perfusion fluidflowing out of the IVC is too low or the CO₂ level is too high, thecontroller 150 can adjust the supply of gas to the gas exchanger 114accordingly. As another example, the controller 150 can control theinfusion of one or more solutions based on the sensor 140 and/or anyother sensor in the system 600. As a still further example, if thecontroller senses that the liver is producing too much CO₂, thecontroller can reduce the temperature of the liver to 35° C. (assumingit was previously being maintained as a higher temperature) to reducethe metabolic rate, and accordingly the rate of CO₂ production or O₂consumption. As yet another example, the controller 150 can modulate gasflow to the gas exchanger 114 based on measurements from one or moresensors in the system 600.

In some embodiments, the controller 150 can be configured to controlaspects of the system 600 as a function of lactate value in theperfusion fluid. In one embodiment, multiple perfusion fluid lactatevalues can be obtained over time. For example, a user can withdraw aperfusion fluid sample and use an external blood gas analyzer todetermine a lactate value and/or the system 600 can use an onboardlactate sensor (e.g., a lactate sensor located in the measurement drain2804). The lactate value can be measured in the IVC or elsewhere and canbe repeated at predetermined time intervals (e.g., every 30 minutes).The controller 150 can analyze the trend of the lactate values overtime. If the lactate is trending down or staying relatively even, thiscan be an indication that the liver is being properly perfused. If thelactate is trending upwards, this can be in indication of improperperfusion, which can result in the controller 150 increasing pump flow,adjusting the rate of infused vasodilator, and/or modifying the gas flowto the gas exchanger 114.

Automating the control process can provide many benefits includingproviding finer control over the parameters of the system, which canresult in a healthier liver and/or reducing the burden on the user.

In some embodiments, the system 600 can include a global positioningdevice to track the geographic location of the system.

C. Exemplary Single Use Module

Turning now to the single use module, an exemplary embodiment isdescribed herein as the single-use module 634, although otherembodiments are possible. As noted above, this portion of the system 600typically contains at least all of the components of the system 600 thatcome into contact with biological material such as the perfusate alongwith various peripheral components, flow conduits, sensors, and supportelectronics used in connection with the same. After the system 600 isused to transport an organ, the single-use module can be removed fromthe system 600 and discarded. A new (and sterile) single-use module canbe installed into the system 600 to transport a new organ. In someembodiments, the module 634 does not include a processor, insteadrelying on the controller 150, which can be distributed between thefront end interface circuit board 636, the power circuit board 720, theoperator interface module 146, and the main circuit board 718, forcontrol. However, in some embodiments, the single-use module can includeits own controller/processor (e.g., on the front end circuit board 637).

Referring to FIGS. 13A-13H, an exemplary single use module 634 is shown.FIGS. 13M-R show another exemplary single use module 634 with analternatively shaped organ chamber 104. Note, however, in some of theviews certain components have been omitted to clarify the drawings(e.g., some of the tubing connectors, ports, and/or clamps have beenomitted).

The single-use module 634 can include a chassis 635 having upper 750 aand lower 750 b sections. The upper section 750 a can include a platform752 for supporting various components. The lower section 750 b cansupport the platform 752 and can include structures for pivotablyconnecting with the multiple use module 650.

The lower chassis section 750 b can include a C-shaped mount 656 forrigidly mounting the perfusion fluid pump interface assembly 300, andthe projection 662 for sliding into and snap fitting with the slot 660.In some embodiments, the lower chassis section 750 b can also providestructures for mounting parts of the perfusion circuit including thefollowing components: gas exchanger 114, heater assembly 110, reservoir160, perfusate flow compliance chambers 184, 186. In some embodiments,the lower chassis section 750 b can also contain, via appropriatemounting hardware, various sensors such as the sensor 140, the flow ratesensors 136, 138 a, 138 b, and the pressure sensors 130 a, 130 b. Thelower chassis section 750 b can also mount the front end circuit board637. This embodiment is exemplary only, and components listed above asbeing part of the lower chassis section 750 b can be located elsewheresuch as in the upper section 750 a (e.g., the pressure sensors 130 a,130 b).

The upper chassis section 750 a can include the platform 752. Theplatform 752 can include handles 753 a and 753 b formed therein toassist in installing and removing the single use module 634 from themultiple use module 650, although the handles can be located elsewherein the single use module 634. The platform 752 can include one or moreorifices (e.g., 717) to allow tubing and/or other components to passtherethrough. The platform 752 can also include one or more integrallyformed brackets (e.g., 716) to hold components in place atop theplatform 752, such as the fluid injection and/or sampling portsdescribed more fully below. The upper chassis section 750 a can alsoinclude a flow clamp 190 for regulating the flow of perfusion fluid tothe portal vein, as described more fully below. The organ chamberassembly 104 can be configured to mount to the platform 752 via one ormore supports 719. Referring specifically to FIG. 13I, the organ chamberassembly 104 can be mounted so that the left and right sides (relativeto the main drain) are at approximately a 15° angle with respect to theplatform 752. Doing so can help perfusion fluid drain from the organchamber assembly 104, especially during transient conditions that can beencountered during transport (e.g., takeoff and landing in an airplane).

1. Organ Chamber

The system 600 can include an organ chamber that is configured to holdan ex vivo organ. The design of the organ chamber can vary depending onthe type of organ. For example, the design of the organ chamber can varydepending on whether, for example, it is being used to transport aliver, a heart, and/or lungs. While the following description focuses onan organ chamber 104 that is configured to transport a liver, thisembodiment is exemplary only, and other configurations are possible. Forexample, other configurations of the organ chamber 104 can also be usedto transport a liver.

a) Shape/Drain Structure

Referring to FIGS. 14A-14H, an exemplary embodiment of the organ chamber104 is shown from multiple views. In this embodiment, the organ chamber104 includes a base 2802, a front piece 2816, a removable lid 2820, anda support surface 2810 (which is described in detail with respect toFIGS. 15A-15D). In some embodiments, the organ chamber 104 can alsoinclude a pad 4500 to support the liver. The bottom of the organ chamber104 can be configured with a quasi-funnel shape where the sides of thefunnel are angled at approximately 15° relative to the platform 752,this is illustrated more clearly in FIG. 13I.

The general level, the base member 2802 can include one or more drains(e.g., 2804, 2806), one more orifices (e.g., 2830) for tubing,connectors, and/or instruments to be inserted inside of the organchamber 104 while the lid (e.g., 2820) is closed, one or more hingeportions (e.g., 2832), and one or more mounting brackets (e.g., 2834).In some embodiments, as shown in FIG. 14I, the mounting brackets 2834are molded. In some embodiments, the base member 2802 is configured tofit and support the support surface 2810, on which the liver typicallyrests. The organ chamber 104 and the support surface 2810 can be madefrom any suitable polymer plastic, for example, polycarbonate.

The base 2802 of chamber 2204 can be shaped and positioned within thesystem 600 to facilitate the drainage of the perfusion medium from theliver 101. The organ chamber 104 can have two drains: measurement drain2804, and main drain 2806, which can receive overflow from themeasurement drain. The measurement drain 2804 can drain perfusate at arate of about 0.5 L/min, considerably less than perfusion fluid 250 flowrate through liver 101 of between and 1-3 L/min. The measurement drain2804 can lead to sensor 140, which can measure SaO₂, hematocrit values,and/or temperature, and then leads on to reservoir 160. The main drain2806 can lead directly to the defoamer/filter 161 without passingthrough the sensor 140. In some embodiments, the sensor 140 cannotobtain accurate measurements unless perfusion fluid 108 is substantiallyfree of air bubbles. In order to achieve a bubble-free column ofperfusate, base 2802 is shaped to collect perfusion fluid 108 drainingfrom liver 101 into a pool that collects above the measurement drain2804. The perfusate pool typically allows air bubbles to dissipatebefore the perfusate enters drain 2804. The formation of a pool abovedrain 2804 can be promoted by optional wall 2808, which can partiallyblock the flow of perfusate from measurement drain 2804 to main drain2806 until the perfusate pool is large enough to ensure the dissipationof bubbles from the flow. Main drain 2806 can be lower than measurementdrain 2804, so once perfusate overflows the depression surrounding drain2804, it flows around and/or over wall 2808, to drain from main drain2806.

In an alternate embodiment of the dual drain system, other systems areused to collect perfusion fluid into a pool that feeds the measurementdrain. In some embodiments, the flow from the liver is directed to avessel, such as a small cup 2838, which feeds the measurement drain. Thecup 2838 fills with perfusion fluid, and excess blood overflows the cupand is directed to the main drain and thus to the reservoir pool. Inthis embodiment, the cup 2838 performs a function similar to that ofwall 2808 in the embodiment described above by forming a small pool ofperfusion fluid from which bubbles can dissipate before the perfusateflows into the measurement drain on its way to the oxygen sensor. Instill other embodiments of the measurement drain, a gradual depressioncan be formed in the bottom of the base 2802 around the measurementdrain 2804 that performs the same function as the cup described above.

The top of organ chamber 104 can be covered with a sealable lid thatincludes front piece 2816, removable lid 2820, inner lid with steriledrape (not shown), and sealing piece 2818. The removable lid 2820 can behingedely and removably coupled to the base member 2802 via hingeportions 2832. The sealing piece 2818 can seal the front piece 2816and/or base 2802 to lid 2820 to create a fluid and/or airtight seal. Thesealing piece 2818 can be made out of, for example, rubber and/or foam.In some embodiments, the front piece 2816 and lid 2820 is rigid enoughto protect the liver 101 from physical contact, indirect or direct.

An alternative embodiment of the organ chamber is shown from multipleviews in FIGS. 14I-S. In this embodiment, the base 2802 of the organchamber 104 has a different shape. FIGS. 14I-14K show a top views, FIGS.14L-14O show side views, FIGS. 14P-14R show bottom views, and FIG. 14Sshows a break out of the alternative embodiment. The organ chamber 104includes a base 2802, an organ support surface 2810, and a removable lid2820.

For example, the top of the organ chamber can be covered with a singlesealable lid 2820. The removable lid can be hingedly and removablycoupled to the organ chamber base member via hinge portions 2832. Thelid is fastened to the base through a series of latches 2836 or othermechanisms. The sealing piece 2818 of the lid can be made of rubberand/or foam, and it can seal the lid to the base to create a fluid orairtight seal. The combination of the lid and base is rigid enough toprotect the liver from direct or indirect physical contact. The organchamber contains orifices (e.g., 2830) for conduit connections forcannulated vessels, including the HA, PV and bile duct. The organchamber contains a structure 2840 positioned above the measurement drain2804 that holds the end of the IVC in place during transport of theorgan. This structure directs the perfusate exiting from the IVC cannulato the measurement drain.

In an alternate embodiment (not shown), the organ chamber 104 caninclude a double lid system that includes an inner lid and an outer lid.More particularly, in one embodiment, the organ chamber assembly caninclude a housing, an outer lid and an intermediate lid. The housing caninclude a bottom and one or more walls for containing the organ. Theintermediate lid can cover an opening to the housing for substantiallyenclosing the organ within the housing, and can include a frame and aflexible membrane suspended within the frame. The flexible membrane canbe transparent, opaque, translucent, or substantially transparent. Insome embodiments, the flexible membrane includes sufficient excessmembrane material to contact an organ contained within the chamber. Thisfeature can enable a medical operator to touch/examine the organindirectly through the membrane while still maintaining sterility of thesystem and the organ. For example, the area of the membrane in theintermediate lid can be 100-300% larger than the area defined by theintermediate lid frame or have an area that is 100-300% larger than atwo-dimensional area occupied by the liver. In some embodiments, theflexible membrane can be selected so that an operator can perform anultrasound of the liver through the membrane while maintaining thesterility and/or environment of the chamber.

In some embodiments, the intermediate lid can be hinged to the housing.The intermediate lid can also include a latch for securing theintermediate lid closed over the opening of the organ chamber. The outerlid may be similarly hinged and latched or completely removable. In someconfigurations, gaskets are provided for forming a fluid and/or airtightseal between the intermediate lid frame and the one or more organchamber walls, and/or for forming a fluid and/or airtight seal betweenthe periphery of the outer lid and the frame of the intermediate lid. Inthis manner, the environment surrounding the liver 101 can be maintainedregardless of whether the outer lid is open.

Covering the organ chamber 104 can serve to minimize the exchange ofgases between perfusion fluid 108 and ambient air, can help ensure thatthe oxygen probes measure the desired oxygen values (e.g., valuescorresponding to perfusate exiting the liver 101), and can help maintainsterility. The closing of organ chamber 2204 can also serve to reduceheat loss from the liver. Heat loss can be considerable because of thelarge surface area of the liver. Heat loss can be an important issueduring transport of the liver when the system 600 may be placed intorelatively low temperature environments, such as a vehicle, or theoutdoors when moving the system 600 into and out of a vehicle.Furthermore, prior to transplantation, system 600 may be temporarilyplaced in a hospital holding area or in an operating theater, both ofwhich typically have temperatures in the range of 15-22° C. At suchambient temperatures, it is important to reduce heat loss from organchamber 2204 in order to allow heater 230 to maintain the desiredperfusate and liver temperature. Sealing the liver 101 in the organchamber 2204 can also help to maintain uniformity of the temperaturethrough liver 101.

Referring also to FIGS. 15A-15D shows an exemplary embodiment of supportsurface 2810 that is configured to support the liver 101. Thisembodiment includes drainage channels 2812, drain 2814, and orifices2815. The drainage channels 2812 are configured to channel perfusatedraining from the liver 101 and guide it toward the drain 2814. In someembodiments, when the support surface 2810 is installed in the base2802, the drain 2814 is located above and/or in the proximity ofmeasurement drain 2804 thereby ensuring that a substantial amount of theperfusate 108 drains from the support surface 2810 into the measurementdrain 2804. The orifices 2815 are configured to provide supplementalareas for the perfusion to drain from the support surface 2810.Additionally, the support surface 2810 can be configured to be used withthe pad 4500 (described below). The support surface 2810 can alsoinclude orifices 2813 that can be used to secure the pad 4500 using, forexample, screws or rivets. In some embodiments, when the support surface2810 is installed in the organ chamber 104, it is installed so that itrests at approximately a 5-degree angle relative to horizontal, althoughother angles can be used (e.g., 0-60 degrees).

Referring to FIGS. 16F-16J, in an alternate embodiment, the supportsurface 4700 is a flexible material that supports and cushions theorgan, and support surface 2810 is omitted. The material is of acomposition such that is provides a compliant, smooth surface on whichthe sensitive liver tissue can rest. The surface can be perforated in amanner, i.e. the number, arrangement and diameter of the perforations,to allow for drainage from the liver while providing an atraumaticsurface for the liver tissue. In this or other embodiments, the support4700 is a layer of materials, including a top layer 4706 and a bottomlayer 4708 of a compliant material 4706 and an inner layer that is aframe 4702 of malleable metal substrate (e.g., aluminum). In someembodiments, the top layer 4706 and bottom layer 4708 can be made out ofpolyurethane foam and/or a cellular silicone foam.

The assembly is supported by the organ chamber base 2802, suspending thesupport surface 4700 above the bottom of the organ chamber base 2802 atan appropriate height to provide displacement by the weight of theorgan. The frame 4702 of the support surface 4700 can be held in placeto the organ chamber base 2802 through the use of fasteners 4704, suchas molded pins, rivets, screws, or other hardware, that are insertedthrough openings 4610 in the frame 4702.

In some embodiments, the malleable metal frame 4702 extends intoprojections 4712. The projections 4712 may also be enclosed by the toplayer 4706 and bottom layer 4708. The projections 4712 can be formedinto positions to surround the liver to stabilize the position of theliver in the x, y and z axes. By bending the projections 4712, the usercan selectively support the liver in a manner that mimics how the liveris supported in the human body. In some embodiments, portions of theframe 4702 can be tapered and terminated with a circle, as shown in FIG.16G. The tapering of the portions of the frame 4702 can: i) allow theprojections 4712 to be curled more easier and reduce, or even eliminate,the possibility of creasing, and ii) reduce weight of the supportsurface 4700. The circle can provide a surface that is easily held bythe user. The tapered shape of the portions of the frame 4702 can bespecifically selected to facilitate its rolling to conform to a naturalarc rather than a fold or bend. The projections 4712 can be of any shapedesired to surround the liver. In use, the liver is placed on the toplayer 4706 of the support surface 4700, allowing the support surface4700 to depress. Then, the projections 4712 may be formed into positionsto surround the liver.

b) Stabilization of Liver

In some embodiments, the liver can be stabilized during transport by oneor more systems that are designed to support and keep the liver in placewithout damaging the liver by applying undue pressure thereto. Forexample, in some embodiments the system 600 can use a soft stabilizingliver pad (e.g., 4500) to support the liver along with a wrap/tarp(e.g., 4600). In some embodiments, the stabilization system can allowsome movement of liver up to a predetermined limit (e.g., the system canallow the liver to move up to 2 inches in any direction). In someembodiments the surface on which the liver rests can have a low frictionsurface, which can also help reduce damage to the liver. The side of thepad in contact with the support surface 2810 can have a high frictionsurface to help hold the pad in place.

The pad can be designed to form a cradle that selectively andcontrollably supports the liver 101 without applying undue pressure tothe liver 101. That is, were the liver 101 merely placed on the supportsurface 2810 without anything more, physical damage could result to theportions of the liver on which the liver is resting during transport.For example, the pad can be formed from a material resilient enough tocushion the liver from mechanical vibrations and shocks duringtransport.

An exemplary embodiment of the stabilizing liver pad and wrap is shownas pad 4500 in FIGS. 16A-16E and wrap 4600 in FIG. 16D. The pad 4500 caninclude two layers: a top layer 4502 and a bottom layer 4504. In someembodiments, the top layer 4502 can be made out of polyurethane foam andthe bottom layer 4504 can be made out of cellular silicone foam. In thisembodiment, the top layer 4502 can be 6 mm thick and the bottom layer4504 can be 3/16″ thick, although other thicknesses and materials can beused. The top layer 4502 and the bottom layer 4504 can be bonded to oneanother using adhesive such as MOMENTIVE Silicone RTV 118 silicone. Theshape of the pad 4500 can be optimized for the liver (e.g., as shown inFIG. 16A). For example, the shape of the pad 4500 can include curvedcorners and one or more fingers (e.g., 4506, 4508, 4510, 4512, 4514, and4516). The pad 4500 can also include one or more holes 4520 throughwhich the pad 4500 can be secured to the support surface 2810 using, forexample, rivets and/or screws. In some embodiments, the pad 4500 can beapproximately 16×12 inches in size, although other sizes are possible.

Sandwiched between the top layer 4502 and the bottom layer 4504 can be adeformable metal substrate 4518. The deformable substrate 4518 can beconstructed out of a rigid yet pliable material such as metal, althoughother materials can be used. In some embodiments, the deformablesubstrate 4518 is aluminum 1100-0 that is 0.04″ thick. The substrate4518 can be configured so that it is manipulated easily by the user, butresists changes to its positioning due to vibration or impact of theliver. The deformable substrate 4518 can include fingers 4522, 4524,4526, 4528, 4530, 4532 that correspond to the fingers 4506, 4508, 4510,4512, 4514, 4516, respectively. By bending the various fingers in thepad 4500, the user can selectively support the liver in a manner thatmimics how the liver supported in the human body. An exemplaryembodiment of the pad 4500 with the fingers in a curled position isshown in FIG. 16D. In some embodiments, each of the fingers in thedeformable substrate 4518 can be tapered (e.g., as shown by 4534) andterminated with a circle. The tapering of the fingers in the substrate4518 can i) allow the fingers to be curled easier and reduce, or eveneliminate the possibility of the finger creasing while being bent, andii) reduce weight of the pad 4500. The circle can provide a surface thatis easily held by the user. The tapered shape of the fingers can bespecifically selected to facilitate a rolling of the pad finger toconform to a natural arc rather than a fold or bend.

Referring to FIGS. 16F-16J, in an alternate embodiment, the stabilizermay be comprised of three layers. The top layer 4706 and the bottomlayer 4708 may be made of cellular silicone foam. Each foam layer can be3/16″ thick, although other thicknesses and materials can be used. Theinner layer is a frame 4702 of a deformable metal substrate in the formof a narrow frame. The frame 4702 can be constructed out of a rigid yetpliable material such as metal, although other materials can be used. Insome embodiments, the frame 4702 is aluminum 1100-0 that is 0.04″ thick.The frame 4702 can be configured so that it is manipulated easily by theuser, but resists changes to its positioning due to vibration or impactof the liver.

The top layer 4706 and the bottom layer 4708 can be bonded to oneanother and to the frame 4702 using adhesive such as MOMENTIVE SiliconeRTV 118 silicone. The top and bottom layers 4706, 4708 cover the areainside the frame 4702, thereby creating a compliant support surface 4700on which the liver is located for transport. The shape of the supportsurface 4700 can be optimized for the liver. For example, the shape ofthe support surface 4700 can include curved corners and one or moreprojections 4712 to constrain the movement of the liver duringtransport. In some embodiments, a wrap 4600 can be placed over the liverto hold it in place during transport and maintain moisture in the liver.For example, as shown in FIG. 16D, the wrap 4600 can be attached to thepad on one side (e.g., the right side in FIG. 16D) and the remainingportion of the wrap can be draped over the liver. In other embodiments,the wrap can be secured on multiple edges or all edges. The wrap 4600may also be used with flexible support surface 4700. In someembodiments, the wrap can perform one or more functions such as securingthe liver during transplant, helping maintain sterility, and preservingthe moisture in the liver by acting as a vapor barrier. The wrap can bemade out of a polyurethane sheet and can be opaque or clear tofacilitate visual inspection of the liver. The size of the wrap 4600 canvary. For example, it can have a length that is between 0.5 and 24inches and a width that is between 0.5 and 24 inches.

2. General Description of Perfusion Circuit

As described above, the liver has two blood supply sources: the hepaticartery and the portal vein, which provide approximately ⅓ and ⅔ of theblood supply to the liver, respectively. Typically, when comparing theblood supply provided by the hepatic artery and the portal vein, thehepatic artery provides a blood supply with a higher pressure yet lowflow rate and the portal vein provides a blood supply with alower-pressure yet high flow rate. Also, typically, the hepatic arteryprovides a pulsatile flow of blood to the liver whereas the portal veindoes not.

The system 600 can be configured to supply perfusion solution to theliver in a manner that simulates the human body (e.g., the properpressures, volumes, and pulsatile flows) using a single pump. Forexample, in a normal flow mode, the system 600 can circulate theperfusion fluid to the liver in the same manner as blood would circulatein the human body. More particularly, the perfusion fluid enters theliver through the hepatic artery and the portal vein and flows away fromthe liver via the IVC. In normal flow mode, the system 100 pumps theperfusion fluid to the liver 102 at a near physiological rate of betweenabout 1-3 L/min, although in some embodiments the range can be 1.1-1.75L/min (although the system can also be configured to provide flow ratesoutside of this range, e.g., 0-10 L/min). Each of the foregoing numbersis the total flow per minute provided to the hepatic artery and portalvein.

Referring to FIG. 17, an exemplary embodiment of a perfusion set 100 isshown. The perfusion set 100 can include a reservoir 160, a one-wayvalve 191, a pump 106, a one-way valve 310, compliance chambers 184,186, a gas exchanger 114, a heater 110, flow meters 136, 138 a, 138 b, adivider 105, a flow clamp 190 pressure sensors 130 a, 130 b, organchamber 104, a sensor 140, defoamer/filter 161, and tubing/interfaces toconnect the same. The liver can also be connected to a bag 187 thecollects bile produced therefrom. In some embodiments, the perfusion set100 is contained entirely within the single use module 634, althoughthis is not required. In some embodiments, the inferior vena cava (IVC)is cannulated so that flow from the IVC can be directed to a conduit inwhich the IVC pressure, flow, and oxygen saturation can be measured. Inother embodiments, the IVC is not cannulated and perfusate flows freelyfrom the IVC into the organ chamber 104 (and ultimately into thedrain(s) in the organ chamber 104).

In one embodiment, perfusion fluid flows from the reservoir 160 to valve191 and then to the pump 106. After pump 106, the perfusion can flow toone-way valve 310 to compliance chamber 184. After compliance chamber184, the perfusion fluid can flow to the gas exchanger 114 and on to theheater 110. After the heater 110 the perfusion fluid can flow to theflow meter 136 which is configured to measure the flow rate at that partof the perfusion circuit. After the flow meter 136 the perfusion fluidflows to the divider 105, which can divide the flow of the perfusionfluid into branches 313 and 315. In some embodiments, the divider 105can split the flow between the hepatic artery and the portal vein at aratio of between 1:2 and 1:3. Branch 313 is ultimately provided to theportal vein of the liver whereas branch 315 is ultimately provided tothe hepatic artery of the liver. The branch 313 can include flow meter138 a and the compliance chamber 186 which provides perfusion fluid tothe flow clamp 190. From the flow clamp 190 the perfusion fluid can flowto the pressure sensor 130 a before being provided to the portal vein ofthe liver. The branch 315 can include a flow meter 138 b which providesperfusion fluid to the pressure meter 130 b before being provided to thehepatic artery of the liver. After perfusion fluid exits the liver, someof the perfusion fluid is collected by the measurement drain 2804 andthe remainder is collected by the main drain 2806. The perfusion fluidcollected by the measurement drain 2804 can be provided to the sensor140. Perfusion fluid exiting the sensor 140 can be provided to thedefoamer/filter 161. The perfusion fluid collected by the drain 2806 canbe provided directly to the defoamer/filter 161. Perfusion fluid exitingthe defoamer/filter 161 can be provided to the reservoir 160.Additionally, bile produced by the liver can be collected in a bag 187.

In some embodiments, the system 100 has at least 1.6 L of perfusionfluid (or other fluid) in it when operating.

3. Reservoir

The single use module 634 can include a perfusate reservoir 160 that ismounted below the organ chamber 104. The reservoir 160 can be configuredto store and filter perfusion fluid 108 as it circulates through theperfusion set 100. Reservoir 160 can include one or more one-way valves(not shown) that prevent the flow of perfusion fluid in the wrongdirection. In some embodiments, the reservoir 160 has a minimum capacityof 2 L, although smaller capacities can be used. In some embodiments,the reservoir 160 can include a filter (shown separately in FIG. 17 asdefoamer/filter 161) that is designed to trap particles in the perfusionfluid 108. In some embodiments, the filter is configured to trapparticles in the perfusion fluid 108 that are greater than 20 microns.In some embodiments, the reservoir 160 includes a defoamer (shownseparately in FIG. 17 as defoamer/filter 161) that reduces and/oreliminates foam generated from the perfusion fluid 108. In someembodiments, the reservoir 160 can be made of a clear material and caninclude level markings so that a user may estimate the volume of theperfusion fluid in the reservoir 160. In some embodiments, the reservoir160 can be configured to allow for a minimum of 4.5 L per minute a fluidingress from the organ chamber 104, although other flow rates arepossible. In some embodiments, the reservoir 160 includes a vent to theatmosphere that includes a sterile barrier (not shown).

The reservoir 160 can be positioned within the system 600 in variouslocations. For example, the reservoir 160 can be located above theliver, completely below the liver, partially below the liver, next tothe liver, etc. Thus, one potential benefit some embodiments describedherein is that the reservoir can be positioned below the liver since agravity-induced pressure head in the perfusion fluid is not required.

4. Valves

In some embodiments, the valves 191 and 310 are one-way valvesconfigured to ensure that the perfusion fluid in the system 100 flows inthe correct direction through the system 100. Exemplary embodiments ofthe valves 191 and 310 are described above with respect to the pump 106.

5. Perfusion Fluid Pump

An exemplary embodiments of the pump 106 is described more fully abovewith respect to FIGS. 6A-6E. As described above, in some embodiments,the pump is split between the multiple use module 650 and the single usemodule 634. For example, the single use module 634 can include the pumpinterface assembly while the multiple use module 650 includes the pumpdriver portion.

6. Compliance Chamber

While the pump 106 provides a generally pulsatile output, thecharacteristics of that flow are typically adapted to match the flowtypically provided by the human body to the liver. For example, theportal vein typically does not provide a pulsatile flow of blood to aliver when the liver is in vivo. Thus, in some embodiments, in order toprovide a non-pulsatile flow of perfusion fluid to the portal vein ofthe liver, one or more compliance chambers can be used to mitigate thepulsatile flow generated by the pump 106. In some embodiments, thecompliance chambers are essentially small in-line fluid accumulatorswith flexible, resilient walls for simulating the human body's vascularcompliance. The compliance chambers can aid the system 600 by moreaccurately mimicking blood flow in the human body, for example, byfiltering/reducing fluid pressure spikes due, for example, to the flowprofile from the pump 106. In the embodiment of system 600 describedherein, two compliance chambers are used: compliance chamber 184 and186. Various characteristics of the compliance chambers can be varied toachieve the desired result. For example, the combination i) a pressureversus volume relationship, and ii) the overall volume of the compliancechamber can affect the performance of the compliance chamber. Preferablythe characteristics of the respective compliance chambers are chosen toachieve the desired effect.

In some embodiments, the compliance chamber 184 is located between thevalve 310 and the gas exchanger 114 and operates to partially smooth thepulsatile output of the pump 106. For example, the compliance chamber184 can be configured such that the flow of perfusion fluid ultimatelyprovided to the hepatic artery of the liver mimics that of the humanbody. In some embodiments, the compliance chamber 184 can be omitted ifthe output of the pump 106 results in a perfusate flow to the hepaticartery that closely mimics that of the human body.

In some embodiments, the compliance chamber 186 is located between thedivider 105 and the flow clamp 190. The compliance chamber 186 canoperate to substantially reduce, or even eliminate the pulsatile natureof the flow of perfusion fluid ultimately provided to the portal vein.Additionally, while the compliance chamber 186 is positioned before theflow clamp 190 in the branch 313, this is not required. For example,flow clamp 190 can come before the compliance chamber 186. In thisembodiment, however, it may be desirable to adjust the parameters of thecompliance chamber 186.

7. Gas Exchanger

The system 600 can also include a gas exchanger 114 (also referred toherein as an oxygenator) that is configured to, for example, remove CO₂from the perfusion fluid and add O₂. The gas exchanger 114 can receiveinput gas from an external or onboard source (e.g., gas supply 172 oroxygen concentrator) through a gas regulator and/or a gas flow chamberwhich can be a pulse-width modulated solenoid valve that controls gasflow, or any other gas control device that allows for precise control ofgas flow rate. In some embodiments, the gas exchanger 114 is a standardmembrane oxygenator, such as the interventional lung assist membraneventilator from NOVALUNG or member of the Quadrox series from Maquet ofWayne, N.J. In the illustrative embodiment, the gas can be a blend ofoxygen, carbon dioxide, and nitrogen. An exemplary blend of gas is: 80%O₂, 0.1% CO₂, and the balance N₂ with a blend process accuracy of0.030%. In some embodiments, the operation of the gas exchanger,regulator, and/or gas flow chamber can be controlled by the controller150 using the output of the sensor 140.

In some embodiments, the oxygenator 114 can have an oxygen transfer rateof 27.5 mLpm/LPM minute at a blood flow of 500 mLpm at standardconditions. The oxygenator 114 can also have a carbon dioxide transferrate of 20 mLpm at a blood flow rate of 500 mLpm at standard conditions.Standard conditions can be, for example: gas=100% O₂, bloodtemp=37.0±0.5° C., hemoglobin=12±1 mg %, SvO₂=65±5%, pCO2=45±5 mmHg, andgas to blood ratio of 1:1). The above values are exemplary only and notlimiting. Transfer rates higher and/or lower than the rate identifiedabove can be used.

8. Heater/Cooler

The perfusion set 100 can include one or more heaters that areconfigured to maintain the temperature of the perfusion fluid 108 at adesired level. By warming the perfusion fluid, and the flowing thewarmed liquid through the liver, the liver itself can also be warmed.While the heater can be capable of warming the perfusion fluid to a widerange of temperatures (e.g., 0-50° C.), typically, the heater warms theperfusion fluid to a temperature of 30-37° C. In some more specificembodiments, the heater can be configured warm the perfusion fluid to atemperature of 34-37° C., 35-37° C., or any other range that fallswithin 0-50° C. In some embodiments, the ranges described herein canalso extend to 42° C.

Referring to FIGS. 18A-18G, an exemplary embodiment of a heater assembly110 is shown. FIGS. 18A-18F depict various views of the perfusion fluidheater assembly 110. The heater assembly 110 can include a housing 234having an inlet 110 a and an outlet 110 b. As shown in both thelongitudinal cross-sectional and the lateral cross-sectional views, theheater assembly 110 can include a flow channel 240 extending between theinlet 110 a and the outlet 110 b. The heater assembly 110 can beconceptualized as having upper 236 and lower 238 symmetrical halves.Accordingly, only the upper half is shown in an exploded view in FIG.18F.

The flow channel 240 can be formed between first 242 and second 244 flowchannel plates. The inlet 110 a can flow the perfusion fluid into theflow channel 240 and the outlet 110 b can flow the perfusion fluid outof the heater 110. The first 242 and second 244 flow channel plates canhave substantially bioinert perfusion fluid 108 contacting surfaces forproviding direct contact with the perfusion fluid flowing through thechannel 240. The fluid contacting surfaces can be formed from atreatment or coating on the plate or may be the plate surface itself.The heater assembly 110 can include first and second electric heaters246 and 248, respectively. The first heater 246 can be located adjacentto and can couple heat to a first heater plate 250. The first heaterplate 250, in turn, can couple the heat to the first flow channel plate242. Similarly, the second heater 248 can be located adjacent to and cancouple heat to a second heater plate 252. The second heater plate 252can couple the heat to the second flow channel plate 244. According tothe illustrative embodiment, the first 250 and second 252 heater platescan be formed from a material, such as aluminum, that conducts anddistributes heat from the first 246 and second 248 electric heaters,respectively, relatively uniformly. The uniform heat distribution of theheater plates 250 and 252 can enable the flow channel plates to beformed from a bioinert material, such as titanium, reducing concernregarding its heat distribution characteristic. The heater assembly 110can also include O-rings 254 and 256 for fluid sealing respective flowchannel plates 242 and 244 to the housing 234 to form the flow channel240. In some embodiments the function of the heater plate and flowchannel plate are combined in a single plate.

The heater assembly 110 can further include first assembly brackets 258and 260. The assembly bracket 258 can mount on the top side 236 of theheater assembly 110 over a periphery of the electric heater 246 tosandwich the heater 246, the heater plate 250 and the flow channel plate242 between the assembly bracket 258 and the housing 234. The bolts 262a-262 j can fit through corresponding through holes in the bracket 258,electric heater 246, heater plate 250 and flow channel plate 242, andthread into corresponding nuts 264 a-264 j to affix all of thosecomponents to the housing 234. The assembly bracket 260 can mount on thebottom side 238 of the heater assembly 110 in a similar fashion to affixthe heater 248, the heater plate 252 and the flow channel plate 244 tothe housing 234. A resilient pad 268 can interfit within a periphery ofthe bracket 258. Similarly, a resilient pad 270 can interfit within aperiphery of the bracket 260. A bracket 272 can fit over the pad 268.The bolts 278 a-278 f can interfit through the holes 276 a-276 f,respectively, in the bracket 272 and thread into the nuts 280 a-280 f tocompress the resilient pad 268 against the heater 246 to provide a moreefficient heat transfer to the heater plate 250. The resilient pad 270can be compressed against the heater 248 in a similar fashion by thebracket 274.

The illustrative heater assembly 110 can include temperature sensors 120and 122 and dual-sensor 124. The dual sensor 124, which in practice caninclude a dual thermistor sensor for providing fault tolerance, canmeasure the temperature of the perfusion fluid 108 exiting the heaterassembly 110, and can provide these temperatures to the controller 150.As described in further detail with respect to the heating subsystem149, the signals from the sensors 120, 122 and 124 can be employed in afeedback loop to control drive signals to the first 246 and/or second248 heaters to control the temperature of the heaters 256 and 248.Additionally, to ensure that heater plates 250 and 252 and, therefore,the blood contacting surfaces 242 and 244 of the heater plates 250 and252 do not reach a temperature that might damage the perfusion fluid,the illustrative heater assembly 110 can also include temperaturesensors/lead wires 120 and 122 for monitoring the temperature of theheaters 246 and 248, respectively, and providing these temperatures tothe controller 150. In practice, the sensors attached to sensors/leadwires 120 and 122 can be RTD (resistance temperature device) based. Thesignals from the sensors attached to sensors/lead wires 120 and 122 canbe employed in a feedback loop to further control the drive signals tothe first 246 and/or second 248 heaters to limit the maximum temperatureof the heater plates 250 and 252. As a fault protection, there can besensors for each of the heaters 246 and 248, so that if one should fail,the system can continue to operate with the temperature at the othersensor.

The heater 246 of the heater assembly 110 can receive from thecontroller 150 drive signals 281 a and 281 b (collectively 281) ontocorresponding drive lead 282 a. Similarly, the heater 248 receives fromthe controller 150 drive signals 283 a and 283 b (collectively 283) ontodrive lead 282 b. The drive signals 281 and 283 control the current to,and thus the heat generated by, the respective heaters 246 and 248. Moreparticularly, as shown in FIG. 18G, the drive leads 282 a includes ahigh and a low pair, which connect across a resistive element 286 of theheater 246. The greater the current provided through the resistiveelement 286, the hotter the resistive element 286 gets. The heater 248operates in the same fashion with regard to the drive lead 282 b.According to the illustrative embodiments, the element 286 has aresistance of about 5 ohms. However, in other illustrative embodiments,the element may have a resistance of between about 3 ohms and about 10ohms. The heaters 246 and 248 can be controlled independently by theprocessor 150.

The heater assembly 110 housing components can be formed from a moldedplastic, for example, polycarbonate, and can weigh less than about onepound. More particularly, the housing 234 and the brackets 258, 260, 272and 274 can all be formed from a molded plastic, for example,polycarbonate. According to another feature, the heater assembly can bea single use disposable assembly.

In operation, the illustrative heater assembly 110 can use between about1 Watt and about 200 Watts of power, and can be sized and shaped totransition perfusion fluid 108 flowing through the channel 240 at a rateof between about 300 ml/min and about 5 L/min from a temperature of lessthan about 30° C. to a temperature of at least 37° C. in less than about30 minutes, less than 25 minutes, less than about 20 minutes, less thanabout 15 minutes, or even less than about 10 minutes, withoutsubstantially causing hemolysis of cells, or denaturing proteins orotherwise damaging any blood product portions of the perfusion fluid.

The heater assembly 110 can include housing components, such as thehousing 234 and the brackets 258, 260, 272 and 274, that are formed froma polycarbonate and weighs less than about 5 lb. In some embodiments,the heater assembly can weigh less than 4 pounds. In the illustrativeembodiment, the heater assembly 110 can have a length 288 of about 6.6inches, not including the inlet 110 a and outlet 110 b ports, and awidth 290 of about 2.7 inches. The heater assembly 110 can have a height292 of about 2.6 inches. The flow channel 240 of the heater assembly 110can have a nominal width 296 of about 1.5 inches, a nominal length 294of about 3.5 inches, and a nominal height 298 of about 0.070 inches. Theheight 298 and width 296 can be selected to provide for uniform heatingof the perfusion fluid 108 as it passes through the channel 240. Theheight 298 and width 296 are also selected to provide a cross-sectionalarea within the channel 240 that is approximately equal to the insidecross-sectional area of fluid conduits that carry the perfusion fluid108 into and/or away from the heater assembly 110. In one embodiment,the height 298 and width 296 are selected to provide a cross-sectionalarea within the channel 240 that is approximately equal to the insidecross-sectional area of the inlet fluid conduit 792 and/or substantiallyequal to the inside cross-sectional area of the outlet fluid conduit794.

Projections 257 a-257 d and 259 a-259 d can be included in the heaterassembly 110 and can be used to receive a heat-activated adhesive forbinding the heating assembly to the multiple-use unit 650.

In addition to the heater 110, the system 100 can also include anadditional heater (not shown) that is placed inside the organ chamber110 to provide heat (e.g., a resistance heater).

9. Pressure/Flow Probes

In some embodiments, the system 600 can include pressure sensors 130 a,130 b and flow sensors 138 a, 138 b. The probes and/or sensors can beobtained from standard commercial sources. For example, the flow ratesensors 136, 138 a, and 138 b can be ultrasonic flow sensors, such asthose available from Transonic Systems Inc., Ithaca, N.Y. The fluidpressure probes 130 a, 130 b can be conventional, strain gauge pressuresensors available from MSI or G.E. Thermometrics. Alternatively, apre-calibrated pressure transducer chip can be embedded into organchamber connectors and connected to the controller 150. In someembodiments, the sensors can be configured to measure mean,instantaneous, and/or peak values flow/pressure values. In embodimentswhere a mean value is calculated, the system can be configured tocalculate the mean pressure using a running average sampled values. Thesensors can also be configured to provide systolic and diastolicmeasurements. While these are shown as separate devices in FIG. 17, insome embodiments, a single device can measure both pressure and flow. Insome embodiments, the sensors can be configured to measure pressuresbetween 0-225 mmHg with an accuracy of ±(7%+10 mmHg) for eachtransducer. In some embodiments the flow sensor can be configured tomeasure flow rates between 0-10 L/min with an accuracy of ±12%+0.140L/min. In some embodiments the pressure and flow sensors can beconfigured to sample the pressure/flow within the cannula tip, withinthe vessel, or in the tubing prior to the cannula.

While there is a single sensor 130 b and a single sensor 130 a, thesesensors can include more than one pressure sensor. For example, in someembodiments, the sensor 130 a can include two pressure sensors forredundancy. In such an embodiment, when both sensors are working thecontroller 150 can average the output of both to determine the actualpressure. In embodiments where one of the two pressure sensors in sensor130 a fails, the controller can ignore the malfunctioning sensor.

As described more fully below with respect to FIGS. 23A-23K, thepressure sensors can be contained in a housing 3010 of the connector3000 (and similarly on the connector 3050).

10. Flow Control

The system 600 can be configured to provide perfusate flow rates varyingfrom 0-10 L/min at the flow sensor 136 (e.g., before the divider 105).In some embodiments, the system can be configured to provide a flow rateof 0.6-4 L/min at the flow sensor 136, or even more specifically,1.1-1.75 L/min at the flow sensor 136. These ranges are exemplary onlyand the flow rate at the sensor 136 can be provided within any rangethat falls within 0-10 L/min. The system 600 can be configured toprovide perfusate flow rates varying from 0-10 L/min, and morespecifically 0.25-1 L/min to the hepatic artery of the liver (e.g., asmeasured by the flow sensor 130 b). These ranges are exemplary only andthe flow rate at hepatic artery can be provided within any range thatfalls within 0-10 L/min. The system 600 can be configured to provideperfusate flow rates varying from 0-10 L/min, and more specifically 0.75to 2 L/min to the portal vein of the liver (e.g., as measured by theflow sensor 130 a). These ranges are exemplary only and the flow rate atthe portal vein can be provided within any range that falls within 0-10L/min.

In some embodiments, the system 100 can be capable of generatingperfusate flow through the perfusion module at rates of 0.3-3.5 L/minwith at least 1.8 Liters of perfusion fluid therein. In someembodiments, the pressure provided to the hepatic artery via the branch315 can be between 25-150 mmHg and more specifically between 50-120mmHg, and the pressure provided to the portal vein via the branch 313can be between 1-25 mmHg and more specifically 5-15 mmHg. These rangesare exemplary only and the respective pressures can be provided withinany range that falls within 5-150 mmHg.

11. Perfusate Sensors

The sensor 140 can sense one or more characteristics of the perfusionfluid flowing from the liver by measuring the amount of light absorbedor reflected by the perfusion fluid 108 when applied atmulti-wavelengths. For example, the sensor 140 can be an O₂ saturation,hematocrit, and/or temperature sensor. FIGS. 19A-19C depict an exemplaryembodiment of the sensor 140. The sensor 140 can include an in-linecuvette shaped section of tube 812 connected to the conduit 798, whichcan have at least one optically clear window through which an infraredsensor can provide infrared light. Exemplary embodiments of the sensor140 can be the BLOP4 and/or BLOP4 Plus probes from DATAMED SRL. Thecuvette 812 can be a one-piece molded part having connectors 801 a and801 b. The connectors 801 a and 801 b can be configured to adjoin toconnecting receptacles 803 a and 803 b, respectively, of conduit ends798 a and 798 b. This interconnection between cuvette 812 and conduitends 798 a and 798 b can be configured so as to provide a substantiallyconstant cross-sectional flow area inside conduit 798 and cuvette 812.The configuration can thereby reduce, and in some embodimentssubstantially removes, discontinuities at the interfaces 814 a and 814 bbetween the cuvette 812 and the conduit 798. Reduction/removal of thediscontinuities can enable the blood based perfusion fluid 108 to flowthrough the cuvette with reduced lysing of red blood cells and reducedturbulence, which can enable a more accurate reading of perfusion fluidoxygen levels. This can also reduce damage to the perfusion fluid 108 bythe system 600, which can ultimately reduce damage done to the organbeing transplanted.

The cuvette 812 can be formed from a light transmissive material, suchas any suitable light transmissive glass or polymer. As shown in FIG.19A, the sensor 140 can also include an optical transceiver 816 fordirecting light waves at perfusion fluid 108 passing through the cuvette812 and for measuring light transmission and/or light reflectance todetermine the amount of oxygen in the perfusion fluid 108. In someembodiments a light transmitter can be located on one side of thecuvette 812 and a detector for measuring light transmission through theperfusion fluid 108 can be located on an opposite side of the cuvette812. FIG. 19C depicts a top cross-sectional view of the cuvette 812 andthe transceiver 816. The transceiver 816 can fit around cuvette 812 suchthat transceiver interior flat surfaces 811 and 813 mate against cuvetteflat surfaces 821 and 823, respectively, while the interior convexsurface 815 of transceiver 816 mates with the cuvette 812 convex surface819. In operation, when UV light is transmitted from the transceiver816, it travels from flat surface 811 through the fluid 108 insidecuvette 812, and is received by flat surface 813. The flat surface 813can be configured with a detector for measuring the light transmissionthrough the fluid 108.

In some embodiments, the sensor 140 can be configured to measure SvO₂ inthe range of 0-99%, although in some embodiments this can be limited to50-99%. To the extent that the sensor 140 also measures hematocrit, themeasurement range can be from 0-99%, although in some embodiments thiscan be limited to 15-50%. In some embodiments, the accuracy of themeasurements made by the sensor 140 can be ±5 units and measurements canoccur at least once every 10 seconds. In embodiments of the sensor 140that also measure temperature, the measurement range can be from 0-50°C.

In some embodiments, the system 600 can also include one or more lactatesensors (not shown) that are configured to measure lactate in theperfusion fluid. For example, a lactate sensor can be placed between themeasurement drain 2804 and the defoamer/filter 161, in branch 315,and/or in branch 313. In this configuration, the system 600 can beconfigured to measure lactate values of the perfusion fluid beforeand/or after processing by the liver. In some embodiments, the lactatesensor can be an in-line lactate analyzer probe. In some embodiments thelactate sensor can also be external to the system 600 and use samples ofthe perfusion fluid withdrawn from a sampling port.

In some embodiments the system 600 can also include one or more sensors(e.g., the sensor 140 and/or other sensors such as a disposable bloodgas analysis probe) to measure pH, HCO3, pO2, pCO2, glucose, sodium,potassium, and/or lactate. Exemplary sensors that can be used to measurethe foregoing values include off-the-shelf probes made by Sphere Medicalof Cambridge, United Kingdom. As described above, the sensor can becoupled to the measurement drain 2804. Alternatively, a piece of tubingcan be used to route perfusion fluid to/from the sensor. Someembodiments of the sensor use calibration fluid before and/or afterperforming a measurement. In embodiments using such sensors, the systemcan include a valve that can be used to control the flow of calibrationfluid to the sensor. In some embodiments, the valve can be manuallyactuated and/or automatically actuated by the controller 150. In someembodiments of the sensor, calibration fluid is not used, which canresult in a continuous sampling of the perfusion fluid.

In addition to using the foregoing sensors in a feedback loop to controlthe system 600, some or all of the sensors can also be used to determinethe viability of the liver for transplant.

In some embodiments, external blood analyzer sensors can also be used.In these embodiments, blood samples can be drawn from ports in thebranches 313, 315 (the ports are described more fully below). The bloodsamples can be provided for analysis using standard hospital equipment(e.g. radiometer) or via point of care blood gas analysis (e.g., I-STAT1from Abbott Laboratories or the Epoc from Alere).

12. Sampling/Infusion Ports

The system 600 can include one or more ports that can be used to samplethe perfusion fluid and/or infuse fluid into the perfusion fluid. Insome embodiments, the ports can be configured to work with standardsyringes and/or can be configured with controllable valves. In someembodiments, the ports can be luer ports. Essentially, the system 100can include infusion/sampling ports at any location therein and thefollowing examples are not limiting.

Referring to FIG. 17, the system 100 can include ports 4301, 4302, 4303,4304, 4305, 4306, 4307, and 4308. The port 4301 can be used to provide abolus injection and/or flush (e.g., a post-preservation flush) to thehepatic artery. The port 4302 can be used to provide a bolus injectionand/or flush (e.g., post-preservation flush) to the portal vein. Theports 4303, 4304, 4305 can be coupled to the respective channels of thesolution pump 631 and can provide infusion to the portal vein (in thecase of 4303 and 4304) and to the hepatic artery (in the case of 4305).The ports 4306 and 4307 can be used to obtain a sample of the perfusionfluid flowing into the hepatic artery and portal vein, respectively. Theport 4308 can be used to sample the perfusion fluid in the IVC (orhepatic veins, depending on how the liver was harvested). In someembodiments, each of the ports can include a valve that the useroperates to obtain a flow from the ports.

The port configuration shown in FIG. 17 is exemplary, and more or fewerports can be used. Additionally, ports can be located in additionallocations such as between the pump 106 and the divider 105, between theorgan chamber and bile bag 187, in the bile bag 187, between the maindrain 2806 and the defoamer/filter 161.

The single use module 634 can also include a tube 774 for loadingpriming solution and the exsanguinated blood from the donor or bloodproducts from a blood bank into the reservoir 160. The priming tube 774can be provided directly to the reservoir 160 and/or it can be locatedso that an end of it empties directly above the drain 2806 in the organchamber 104. The single use module 634 can also include non-vented capsfor replacing vented caps on selected fluid ports that are used, forexample, while running a sterilization gas through the single use module634.

Some embodiments the system 100 can also include vents and/or air purgeports to eliminate air from the hepatic artery interface, the portalvein interface, or elsewhere in the system 100.

In some embodiments an extra infusion port can be included for the userto provide an imaging contrast medium to the perfusion fluid so thatimaging of the liver can be enhanced. For example, an ultrasoundcontrast medium can be infused to perform a contrast-enhancedultrasound.

13. Organ Assist

While perfusion fluid can drain naturally from the liver as a result ofthe pressure applied to the hepatic artery and portal vein, the system600 can also include additional features that help the perfusion fluiddrain from the liver in a manner that mimics the human body. That is, inthe human body the diaphragm typically applies pressure to the liver asthe person breathes. This pressure can help expel blood from theperson's liver. The system 600 can include one or more systems that aredesigned to mimic the pressure applied by the diaphragm to the liver.Exemplary embodiments include contact and contactless embodiments. Insome embodiments, the amount of pressure applied to the liver can beless than the pressure in the portal vein and/or hepatic artery of theliver. Sketches of exemplary embodiments of the organ assist systems areshown in FIG. 30.

One embodiment of a contactless pressure system is a system that variesthe air pressure in the organ chamber 104 to simulate pressure appliedby the diaphragm to the liver. In this embodiment, the organ chamber 104can be configured to provide a substantially airtight environment suchthat the air pressure inside the organ chamber 104 can be maintained atan elevated (or lowered) state when compared to the outside atmosphere.As the air pressure in the organ chamber 104 rises, it can applypressure to the liver that simulates the pressure applied by thediaphragm thereby increasing the rate at which the liver expelsperfusion fluid. In some embodiments, the air pressure can be varied ina manner that mimics a human breathing rate (e.g., 12-15 times perminute), or at other rates (e.g., 0.5 to 50 times per minute). The airpressure in the organ chamber 104 can be varied by various methodsincluding, for example, a dedicated air pump (not shown) and/or theonboard gas supply 172. In some embodiments, the air pressure inside theorgan chamber 104 can be controlled by the controller 150. In theseembodiments, the controller can also be coupled to an air pressuresensor measuring the pressure inside the organ chamber 104 that is usedas part of a feedback control loop.

One embodiment of a contact pressure system is a system that that uses awrap and/or bladder to apply pressure to the liver. For example, a wrapcan be placed over some or all of the liver within the organ chamber104. The edges of the wrap can then be mechanically tightened to applypressure to the portion of the liver covered by the wrap. In thisexample, one or more small motors attached to various points around theperiphery of the wrap can be used to tighten the edges of the wrap. Inanother example of a contact pressure system, a removable bladder can beused (not shown). In this embodiment, an inflatable bladder can beplaced between the liver and the top surface (or some other portion) ofthe organ chamber 104. A pump can then be used to inflate/deflate thebladder. As the bladder inflates, it can press against the top surface(or other portion) of the organ chamber 104 thereby exerting pressure onthe liver contained therein. As with the contactless system describedabove, the pressure applied to the liver can be applied periodically tomimic the natural pressure provided by the diaphragm. In someembodiments, the pressure applied to the liver can be varied in a mannerthat mimics human breathing rate (e.g., 12-15 times per minute), or atother rates (e.g., 0.5 to 50 times per minute). Regardless of whetherthe pressure is applied to the liver using a wrap or a bladder, thepressure can be controlled by the controller 150. In some embodiments,one or more sensors that measure the pressure applied to the liver canbe included in the organ chamber 104 as part of a feedback control loop.Other methods of providing contact pressure to the liver are alsopossible.

14. Cannulation

Operationally, in one embodiment, a liver can be harvested from a donorand coupled to the system 600 by a process of cannulation. For example,interface 162 can be cannulated to vascular tissue of the hepatic arteryvia a conduit located within the organ chamber assembly. Interface 166can be cannulated to vascular tissue of the portal vein via a conduitlocated within the organ chamber assembly. The liver emits the perfusatethrough the inferior vena cava (IVC). In some embodiments, the IVC canbe cannulated by interface 170 (not shown) so that the flow can bedirected to a conduit in which the IVC pressure, flow and oxygensaturation can be measured. In another embodiment, the IVC can becannulated by the interface 170 to direct the flow within the organchamber. In still another embodiment, the IVC is not cannulated and theorgan chamber provides a means to direct the perfusate flow forefficient collection to the reservoir.

Each of the interfaces 162, 166 and 170 can be cannulated to the liverby pulling vascular tissue over the end of the interface, then tying orotherwise securing the tissue to the interface. The vascular tissue ispreferably a short segment of a blood vessel that remains connected tothe liver after the liver is severed and explanted from the donor. Insome embodiments, the short vessel segments can be 0.25-5 inches,although other lengths are possible.

Referring to FIGS. 21A-21D, an exemplary embodiment of a hepatic arterycannula 2600 is shown. The cannula 2600 is generally tubular in shapeand includes a first portion 2604 that is configured to be inserted intotubing used in the system 100 and includes a first orifice 2612. Thefirst portion 2604 can also include a ring 2602 that can be used to helpsecure the first portion 2604 inside of the tubing of the system 100 byfriction. The cannula 2600 can also include a second portion 2608 thatcan have a smaller diameter than the first portion 2604 and that forms asecond orifice 2614. The second portion 2608 can also include a channel2610 that is recessed from the surface of the second portion 2608. Insome embodiments, when the user ties the hepatic artery to the secondportion 2608, the user can place the suture in the channel 2610 to helpsecure the hepatic artery. Between the first and second portions can bea collar 2606. The outside diameter of the collar can have a slightlylarger diameter than the first portion 2604 to prevent the tubing of thesystem 100 from extending over the second portion 2608 when inserted.Viewing the cross-section shown in FIG. 21D, the inside diameter of thecannula 2600 can vary, with a taper 2616 therebetween. The cannula 2600can be formed in various sizes, lengths, inside diameters, and outsidediameters. In some embodiments of the system 600, it can be advantageousto have a substantially large inside diameter in the first portion 2604and a much smaller inside diameter in the second portion 2608 to offsetpressure and flow changes caused by the cannula 2600.

Referring to FIGS. 21H-21K, in an alternative embodiment the cannula2600 has a beveled cut end 2618.

The outside diameter of the first portion 2604 can be configured to bepress-fit inside of silicone or polyurethane tubing. Thus, while theoutside diameter of the first portion 2604 can vary, one exemplary rangeof possible diameters is 0.280-0.380″. The outside diameter of thesecond portion 2608 can range between 4-50 Fr, but more specificallybetween 12-20 Fr. Additionally, the cannula 2600 can be made fromvarious biocompatible materials, such as stainless steel, titanium,and/or plastic (the dimensions of the cannula 2600 can be adapted to bemanufacturable using different materials).

Additionally 10-20% of the population have a genetic variation where theliver includes an accessory hepatic artery. For these instances, thehepatic artery cannula described above can be a double-headed (e.g.,Y-shaped) cannula. An exemplary embodiment of a Y-shaped hepatic arterycannula 2642, is shown in FIGS. 21E-21G, where like numbers are used todenote corresponding features in the cannula 2600. The bifurcated designof hepatic artery cannula 2642 can allow the system 100 to treat bothvessels as one input for hepatic artery flow without changing theconfiguration of the system 100 and/or the controller 150.

In an alternative embodiment, when the liver includes an accessoryhepatic artery, two hepatic artery cannulas 2600 may be attached to asection of Y-shaped tubing at one end, and the other end may beconnected to the organ chamber.

Referring to FIGS. 22A-22D, an exemplary embodiment of a portal veincannula 2650 is shown. The cannula 2650 is generally tubular in shapeand includes a first portion 2654 that is configured to be inserted intotubing used in the system 100 and includes a first orifice 2660. Thefirst portion 2654 can also include a ring 2652 that can be used to helpsecure the first portion 2654 inside of the tubing of the system 100 byfriction. The cannula 2650 can also include a second portion 2656 thatcan have a larger diameter than the first portion 2654 and that forms asecond orifice 2662. The second portion 2656 can also include a channel2658 that is recessed from the surface of the second portion 2656. Insome embodiments, when the user ties the portal vein to the secondportion 5626, the user can place the suture in the channel 2658 to helpsecure the portal vein. Viewing the cross-section shown in FIG. 22D, theinside diameter of the cannula 2600 can vary, with a taper 2664therebetween. The cannula 2650 can be formed in various sizes, lengths,inside diameters, and outside diameters. In some embodiments of thesystem 600, it can be advantageous to have a substantially large insidediameter in the first portion 2654 and an even larger inside diameter inthe second portion 2656 to offset pressure and flow changes caused bythe cannula 2650.

Referring to FIGS. 22E-22G. in an alternative embodiment the cannula2650 has a collar 2666 between the first and second portions. Theoutside diameter of the collar can have a slightly larger diameter thanthe first portion 2654 to prevent the tubing of the system 100 fromextending over the second portion 2656 when inserted. The cannula 2650may also have a beveled cut end 2668.

The outside diameter of the first portion 2654 can be configured to bepress-fit inside of silicone or polyurethane tubing. Thus, while theoutside diameter of the first portion 2654 can vary, one exemplary rangeof possible diameters is 0.410-0.510″. The outside diameter of thesecond portion 2656 can range between 25-75 Fr, but more specificallybetween 40-48 Fr. Additionally, the cannula 2650 can be made fromvarious biocompatible materials, such as stainless steel, titanium,and/or plastic (the dimensions of the cannula 2600 can be adapted to bemanufacturable using different materials).

Referring to FIGS. 23A-23N, an exemplary hepatic artery connector 3000is shown. The connector 3000 can be part of the branch 315 leading tothe hepatic artery of the liver. For example, the connector 3000 can beinserted into and secured to the wall of the organ chamber 104. Theconnector 3000 can include a first portion 3006 that includes acircumferential channel 3007 and defines an opening 3008. In someembodiments, the outside diameter of the first portion 3006 is sized tocouple to ¼″ tubing, although other diameters are possible. In someembodiments, tubing coupled to the first portion 3006 can coupled usingfriction and/or a common zip tie (or other similar fastener) can be tiedaround the channel 3007 to secure the tubing connected thereto. Theconnector 3000 can also include a second portion 3002 that defines anopening 3003. In some embodiments, the outside diameter of the secondportion 3002 can be configured to couple to ¼″ tubing using apress/friction connection, although other sizes are possible. In someembodiments, perfusion fluid flows from the opening 3008 toward theopening 3003.

The connector 3000 can include an interface that is configured to matewith an opening in a wall of the organ chamber 104. For example,connector 3000 can include a ridge 3003 that is sized to fit within acorresponding opening in a wall of the organ chamber 104. A backstop3004 can be larger than the opening to prevent the connector from beinginserted too far, and can also provide a surface on which adhesive canbe applied to bond the connector 3000 to the organ chamber 104. In someembodiments, the ridge 3003 can include a protrusion 3011 that isconfigured to rotationally align the connector 3000 within the organchamber 104. For example, in some embodiments, the protrusion 3011 andcorresponding opening in the organ chamber 104 can be configured so thatthe connector 3000 is rotated about a longitudinal axis of the secondportion 3003. In some embodiments, the rotation can be optimized toprevent air bubbles.

The connector 3010 can also including a housing 3010 that is configuredto house the pressure sensor 130 b. In this embodiment the two pressuresensors make up the pressure sensor 130 b. In such an embodiment, thepressure sensors can be mounted in the openings 3009, which can providedirect access to the fluid within the connector 3000. Additionally, someembodiments of the connector 3000 can include an air vent 3005 that canbe connected to a valve which can be opened to vent air bubbles trappedwithin the connector 3000. In operation, a user can attach one end of atube to the second portion 3002 and the other end of the tube to thehepatic artery cannula 2600 (which can be connected to the hepaticartery). In some embodiments, the user can place a liver into the organchamber 104, connect a cannula 2600 to an end of a piece of tubing,which can be connected to the hepatic artery using a suture. Next,because the size of the liver can vary, the user can then trim thetubing to the proper length and attach it to the second portion 3003.

Referring to FIGS. 24A-23L, an exemplary portal vein connector 3050 isshown. In some embodiments the portal vein connector 3050 is configuredand functions in the same manner as the connector 3000, except that thefirst and second portions can be coupled to connect to ⅜″ or ½″ tubinginstead of ¼″, although it can be configured to work with other sizetubing as well. Also, as should be clear by the name, the portal veinconnector can be configured to couple the branch 313 to the portal veinof the liver.

While some dimensions are provided above, these dimensions are exemplaryonly and each of the foregoing components can sized as necessary toachieve the desired flow characteristics. For example, in someembodiments, it can be beneficial to use the largest diameter cannula toavoid introducing undesirable pressure or flow changes. Additionally, inpractice, the diameter of the cannula can be chosen by the surgeon suchthat the largest cannula is used that will physically fit in the vessel.

It is noted herein that some consider the “Fr” scale to end at “34.”Thus, to the extent that a Fr size larger than 34 is identified (or anFr. number that does not exist in the traditional Fr. scale), the sizein mm can be calculated by dividing the identified Fr number by 3.

15. Flow Clamp

Referring to FIGS. 25A-25B, an exemplary embodiment of the flow clamp190 is shown. The flow clamp 190 can be used to control the flow and/orpressure of the perfusion fluid to the portal vein of the liver. Theflow clamp 190 can include a cover 4001, a knob 4002, a pivot 4003, apin 4004 a screw 4005, a bearing 4006, a slide 4007, an axle 4008, and abody 4009. The slide 4007 can include a groove 4010 and detent 4012 andcan be configured to move up and down within the body 4009. In someembodiments, a tube carrying perfusion fluid is placed within the body4009 under the slide 4007. FIGS. 25C-25D show the flow clamp 190 withmolded components.

The flow clamp 190 can be configured to allow a user to quickly engageand disengage the clamp 190, while still having precise control over theamount of clamping force applied. In this embodiment, the cover 4001,the knob 4002, the pivot 4003, the pin 4004, the screw 4005, and thebearing 4006 make up a switch unit 4011. The pivot 4003 of the switchunit 4011 can rotate about a longitudinal axis formed by the axle 4008(which can be made up of two separate screws). In this manner, when theswitch unit 4011 is engaged (e.g., the screw 4005 is vertical), as shownin FIG. 25A, the bearing 4006 forces the slide 4007 downward in the body4009 (which can compress the tube carrying the perfusion fluid, ifpresent, and restricts flow therein). How far down the slide is forcedis a function of how extended the screw 4005 is relative to the pivot4003. When the switch unit 4011 is disengaged, it is pivoted sideways sothat the screw is no longer vertical and does not restrict the movementof the slide 4007. When the switch unit 4011 is pivoted, the bearing canslide along the grove 4010. In some embodiments, the switch unit 4011can “lock” into place when the bearing 4006 comes to rest in the detent4012. The user can adjust the amount of flow restriction is imposed bythe flow clamp 190 when engaged by rotating the knob 4002, therebyextending/retracting the screw 4005. In some embodiments, the pitch ofthe screw can be 4-40 thread, although other pitches can be used adjustthe precision of the flow clamp 190.

16. Priming

In some embodiments, the perfusion fluid includes packed red blood cellsalso known as “bank blood.” Alternatively, the perfusion fluid includesblood removed from the donor through a process of exsanguination duringharvesting of the liver. Initially, the blood is loaded into thereservoir 160 and the cannulation locations in the organ chamberassembly are connected with a bypass conduit to enable normal mode flowof perfusion fluid through the system without a liver being present, aka“priming tube.” Prior to cannulating the harvested liver, the system maybe primed by circulating the exsanguinated donor blood through thesystem to heat, oxygenate, and/or filter it. Nutrients, preservatives,and/or other therapeutics may also be provided during priming via theinfusion pump of the nutritional subsystem. During priming, variousparameters may also be initialized and calibrated via the operatorinterface during priming. Once primed and running appropriately, thepump flow can be reduced or cycled off, the bypass conduit is removedfrom the organ chamber assembly, and the liver can be cannulated intothe organ chamber assembly. The pump flow can then be restored orincreased, as the case may be. The priming process is described morefully below.

17. IVC Cannulation

In some embodiments, the inferior vena cava (IVC) can be cannulated,though not required. In these embodiments, additional pressure and/orflow sensors can be used to determine the pressure and/or flow of theperfusion fluid flowing from the liver. In some embodiments, thecannulated IVC can be coupled directly to the sensor 140 and/orreservoir. In other embodiments, the IVC can be cannulated for thepurpose of directing the drainage of the perfusion fluid (e.g., directedfree draining). For example, the uncannulated end of a short tubeconnected to the IVC can be held in place by a clip so that perfusionfluid drains directly over the measurement drain 2804. In otherembodiments, the IVC is not cannulated and perfusion fluid can drainfreely therefrom. In still other embodiments, the IVC can be partiallytied off.

In embodiments where the IVC is cannulated and connected to tubing, itcan be desirable to keep the length of tubing as short as possible toachieve the desired result. That is, because physiologic IVC pressure islow, even a length of narrow tube can result in an elevated IVCpressure. In embodiments of the system 600 that include pressureexertion on the liver to encourage draining (e.g., pressurizing thechamber 104 as discussed above), the liver may be able to tolerate alonger cannula/tubing.

18. Bile Duct Cannulation

In some embodiments of the system 600, the bile duct of the liver can becannulated using an off the shelf and/or custom cannula. For example, abile duct cannula of 14 Fr can be used. Additionally, the bile bag 187can be configured to collect bile produced by the liver. In someembodiments, the bag 187 is clear so the user can visually observe thecolor of the bile. In some embodiments, the bag 187 can collect up to0.5 L of bile, although other amounts are possible. In some embodiments,the bag 187 can include graduations that indicate how much bile has beencollected. While the system 600 is described as including a soft shell(e.g., the bag 187) to collect bile, a hard shell container can also beused. Some embodiments of the system 600 can include a sensor (e.g.,capacitive, ultrasonic, and/or cumulative flow rate) to measure thevolume of bile collected. This information can then be displayed to theuser and/or sent to the Cloud.

19. Blood Collection/Filter

Some embodiments of the system 600 using whole blood from a donor caninclude leukocyte filter (not shown). In these embodiments, theleukocyte filter can be used when priming the system to filter bloodreceived from a donor body via a blood collection line connected to adonor's artery and/or vein. In some embodiments, the leukocyte filtercan be configured to filter at least 1500 mL of blood in 6 minutes orless (although other rates are possible). In some embodiments, theleukocyte filter can be configured to remove 30% or more of allleukocytes in up to 1500 mL of whole blood.

20. Final Flush Administration Kit

At times during operation, it can be desirable to remove all of theperfusion solution from the liver vasculature (e.g., before the liver isimplanted into a recipient) without disconnecting the liver from thesystem 100. Thus, embodiments of the system 600 can be used with a finalflush administration kit. The kit can include a bag (or other container)to collect a volume of liquid (e.g., flush solution and/or perfusate) sothat when the flushing solution is administered to the liver (e.g., viaports 4301, 4302), the system 100 is not overwhelmed by the additionalvolume of fluid. Thus, in some embodiments, the system 100 can include adrain line (not shown) that can be used to drain fluid from thereservoir 160 and/or elsewhere in the system 100 in such a manner thatthe liver need not be disconnected from the system 100 before addingadditional fluid. In some embodiments, the system can also be setup in abypass operation where the liver is temporarily isolated from the system100 using one or more valves. For example, in this embodiment, valvescan be used before the ports 4301, 4302 to stop fluid flow within thesystem 100. Additional drainage ports can then be included between thedrains 2804, 2806 and the valves. In this embodiment, the flush solution(or any other solution) can be provided via the ports 4301, 4302 anddrain out of the additional drainage ports without being circulated inthe rest of the system 100. In some embodiments, the drain line can holdat least 3 L of liquid, although this is not required.

D. Interface Between Single/Multi Use Modules

As shown in FIG. 3G and described in further detail below, the multipleuse module 650 can include a front-end interface circuit board 636 forinterfacing with a front-end circuit board (shown in FIG. 13J at 637) ofthe disposable module 634. As described more fully below, power anddrive signal connections between the multiple use module 650 and thedisposable module 634 can be made by way of correspondingelectromechanical connectors 640 and 647 on the front end interfacecircuit board 636 and the front end circuit board 637, respectively. Byway of example, the front-end circuit board 637 can receive power forthe disposable module 634 from the front-end interface circuit board 636via the electromechanical connectors 640 and 647. The front end circuitboard 637 can also receive drive signals for various components (e.g.,the heater assembly 110, the flow clamp 190, and the oxygenator 114)from the controller 150 via the front-end interface circuit board 636and the electromechanical connectors 640 and 647. The front-end circuitboard 637 and the front-end interface circuit board 636 can exchangecontrol and data signals (e.g., between the controller 150 and thesingle use module 634) by way of optical connectors (shown in FIG. 20Bat 648). As described in more detail below, the connector configurationemployed between the front-end 637 and front-end interface 636 circuitboards can ensure that critical power and data interconnections betweenthe single and multiple use modules 634 and 650, respectively, continueto operate even during transport over rough terrain, such as may beexperienced during organ transport.

Turning now to the installation of the single use module 634 into themultiple use module 650, FIG. 3H shows a detailed view of theabove-mentioned bracket assembly 638 located on the multiple use module650 for receiving and locking into place the single use module 634. FIG.3F shows a side perspective view of the single use module 634 beinginstalled onto the bracket assembly 638 and into the multiple use module650, and FIG. 3C shows a side view of the single use module 634installed within the multiple use module 650. The bracket assembly 638includes two mounting brackets 642 a and 642 b, which can mount to aninternal side of a back panel of the housing 602 via mounting holes 644a-644 d and 646 a-646 d, respectively. A cross bar 641 extends betweenand rotatably attaches to the mounting brackets 642 a and 642 b. Lockingarms 643 and 645 are spaced apart along and radially extend from thecross bar 641. Each locking arm 643 and 645 includes a respectivedownward extending locking projection 643 a and 645 b. A lever 639attaches to and extends radially upward from the cross bar 641.Actuating the lever 639 in the direction of the arrow 651 rotates thelocking arms 643 and 645 toward the back 606 b of the housing 602.Actuating the lever 639 in the direction of the arrow 653 rotates thelocking arms 643 and 645 toward the front of the housing 602.

As described above with respect to FIG. 6E, the perfusion pump interfaceassembly 300 includes four projecting heat staking points 321 a-321 d.During assembly, the projections 321 a-321 d are aligned withcorresponding apertures (e.g., 657 a, 657 b in FIG. 13B) and heat stakedthrough the apertures to rigidly mount the outer side 304 of the pumpinterface assembly 300 onto the C-shaped bracket 656 of the single usemodule chassis 635.

During installation, in a first step, the single use module 634 islowered into the multiple use module 650 while tilting the single usemodule 634 forward (shown in FIG. 3F). This process slides theprojection 662 into the slot 660. As shown in FIG. 6E, it also positionsthe flange 328 of the pump interface assembly 300 within the dockingport 342 of the perfusion pump assembly 106, and the tapered projections323 a and 323 b of the pump interface assembly 300 on the clockwise sideof corresponding ones of the features 344 a and 344 b of the pumpassembly bracket 346. In a second step, the single use module 634 isrotated backwards until locking arm cradles of the single use modulechassis 635 engage projections 643 and 645 of spring-loaded locking arm638, forcing the projections 643 and 645 to rotate upward, until lockingprojections 643 a and 645 a clear the height of the locking arm cradles,at which point the springs cause the locking arm 638 to rotate downward,allowing locking projections 643 a and 645 a to releasably lock withlocking arm cradles of the disposable module chassis 635. This motioncauses the curved surface of 668 of the single use module projection 662of FIG. 13B to rotate and engage with a flat side 670 of the basin slot660 of FIG. 20B. Lever 639 can be used to rotate the locking arm 638upwards to release the single use module 635.

As shown in FIG. 6E, this motion also causes the pump interface assembly300 to rotate in a counterclockwise direction relative to the pumpassembly 106 to slide the flange 328 into the slot 332 of the dockingport 342, and at the same time, to slide the tapered projections 323 aand 323 b under the respective bracket features 344 a and 344 b. As thetapered projections 323 a and 323 b slide under the respective bracketfeatures 344 a and 344 b, the inner surfaces of the bracket features 344a and 344 b engage with the tapered outer surfaces of the taperedprojections 323 a and 323 b to draw the inner side 306 of the pumpinterface assembly 300 toward the pump driver 334 to form the fluidtight seal between the pump interface assembly 300 and the pump assembly106. The lever 639 may lock in place to hold the disposable module 634securely within the multiple use module 650.

Interlocking the single use module 374 into the multiple use module 650can form both electrical and optical interconnections between the frontend interface circuit board 636 on the multiple use module 650 and thefront end circuit board 637 on the single use module 634. The electricaland optical connections enable the multiple use module 650 to power,control and collect information from the single module 634. FIG. 20A isan exemplary conceptual drawing showing various optical couplers andelectromechanical connectors on the front end circuit board 637 of thesingle-use disposable module 634 used to communicate with correspondingoptical couplers and electromechanical connectors on the front endinterface circuit board 636 of the multiple use module 650. Since thiscorrespondence is one for one, the various optical couplers andelectromechanical connectors are described only with reference to thefront end circuit board 637, rather than also depicting the front endcircuit board 650.

According to the exemplary embodiment, the front end circuit board 637receives signals from the front end interface circuit board 636 via bothoptical couplers and electromechanical connectors. For example, thefront end circuit board 637 receives power 358 from the front endinterface circuit board 636 via the electromechanical connectors 712 and714. The front end circuit board 637 applies the power to the componentsof the single use module 634, such as the various sensors andtransducers of the single use module 634. Optionally, the front endcircuit board 637 converts the power to suitable levels prior todistribution. The front end interface circuit board 636 can also providethe heater drive signals 281 a and 281 b to the applicable connections282 a on the heater 246 of FIG. 6E via the electromechanical connectors704 and 706. Similarly, the electromechanical connectors 708 and 710 cancouple the heater drive signals 283 a and 283 b to the applicableconnections in 282 b of the heater 248.

According to the exemplary embodiment, the front end circuit board 637can receive signals from temperature, pressure, fluid flow-rate, andoxygenation/hematocrit sensors, amplify the signals, convert the signalsto a digital format, and provide them to the front-end interface circuitboard 636 by way of electrical and/or optical couplers. For example, thefront end circuit board 637 can provide the temperature signal 121 fromthe sensor 120 on the heater plate 250 to the front end interfacecircuit board 636 by way of the optical coupler 676. Similarly, thefront end circuit board 637 can provide the temperature signal 123 fromthe sensor 122 on the heater plate 252 to the front end interfacecircuit board 636 by way of the optical coupler 678. The frontend-circuit board 637 can also provide the perfusion fluid temperaturesignals 125 and 127 from the thermistor sensor 124 to the front endinterface circuit board 636 via respective optical couplers 680 and 682.Perfusion fluid pressure signals 129, 131 and 133 can be provided fromrespective pressure transducers 126, 128 and 130 to the front endinterface circuit board 636 via respective optical couplers 688, 690 and692. The front end circuit board 637 can also provide perfusion fluidflow rate signals 135, 137 and 139 from respective flow rate sensors134, 136 and 138 to the front end interface circuit board 636 by way ofrespective optical couplers 694, 696 and 698. Additionally, the frontend circuit board 637 can provide the oxygen saturation 141 andhematocrit 145 signals from the sensor 140 to the front end interfacecircuit board 636 by way of respective optical couplers 700 and 702. Inanother implementation, the front end circuit receives signals fromintegrated blood gas analysis probes. In another implementation thefront end board passes control signals to a fluid path restrictor tofacilitate real time control of the division of perfusate flow betweenthe portal vein and hepatic artery conduits. The controller 150 canemploy the signals provided to the front end interface circuit board636, along with other signals, to transmit data and otherwise controloperation of the system 600.

While the front end circuit board 637 is described with the foregoingcouplers, more or fewer couplers can be used based on the number ofconnections necessary.

In some exemplary embodiments, one or more of the foregoing sensors canbe wired directly to the main system board 718 for processing andanalysis, thus by-passing the front-end interface board 636 andfront-end board 637 altogether. Such embodiments can be desirable wherethe user prefers to re-use one or more of the sensors prior to disposal.In one such example, the flow rate sensors 134, 136 and 138 and theoxygen and hematocrit sensor 140 are electrically coupled directly tothe system main board 718 through electrical coupler 611 shown in FIG.23C, thus by-passing any connection with the circuit boards 636 and 637.

FIG. 20B illustrates the operation of an exemplary electromechanicalconnector pair of the type employed for the electrical interconnectionsbetween the circuit boards 636 and 637. Similarly, FIG. 20C illustratesthe operation of an optical coupler pair of the type employed for theoptically coupled interconnections between the circuit boards 636 and637. One advantage of both the electrical connectors and opticalcouplers employed is that they ensure connection integrity, even whenthe system 600 is being transported over rough terrain, for example,such as being wheeled along a tarmac at an airport, being transported inan aircraft during bad weather conditions, or being transported in anambulance over rough roadways. The power for the front end board 637 isisolated in a DC power supply located on the front end interface board636.

As shown in FIG. 20B, the electromechanical connectors, such as theconnector 704, include a portion, such as the portion 703, located onthe front end interface circuit board 636 and a portion, such as theportion 705, located on the front end circuit board 637. The portion 703includes an enlarged head 703 a mounted on a substantially straight andrigid stem 703 b. The head 703 includes an outwardly facingsubstantially flat surface 708. The portion 705 includes a substantiallystraight and rigid pin 705 including an end 705 a for contacting thesurface 708 and a spring-loaded end 705 b. Pin 705 can move axially inand out as shown by the directional arrow 721 while still maintainingelectrical contact with the surface 708 of the enlarged head 703 a. Thisfeature enables the single use module 634 to maintain electrical contactwith the multiple use module 650 even when experiencing mechanicaldisturbances associated with transport over rough terrain. An advantageof the flat surface 708 is that it allows for easy cleaning of theinterior surface of the multiple use module 650. According to theillustrative embodiment, the system 600 employs a connector for theelectrical interconnection between the single use disposable 634 andmultiple use 650 modules. An exemplary connector is part no. 101342 madeby Interconnect Devices. However, any suitable connector may be used.

Optical couplers, such as the optical couplers 684 and 687 of the frontend circuit board 637, are used and include corresponding counterparts,such as the optical couplers 683 and 685 of the front end interfacecircuit board 636. The optical transmitters and optical receiverportions of the optical couplers may be located on either circuit board636 or 637.

As in the case of the electromechanical connectors employed, allowabletolerance in the optical alignment between the optical transmitters andcorresponding optical receivers enables the circuit boards 636 and 637to remain in optical communication even during transport over roughterrain. According to the illustrative embodiment, the system 100 usesoptical couplers made under part nos. 5FH485P and/or 5FH203 PFA byOsram. However, any suitable coupler may be used.

The couplers and connectors can facilitate the transmission of datawithin the system 600. The front-end interface circuit board 636 and thefront-end board 637 transmit data pertaining to the system 600 in apaced fashion. As shown in FIG. 20C, circuit board 636 transmits to thefront-end board 637 a clock signal that is synchronized to the clock onthe controller 150. The front-end circuit board 637 receives this clocksignal and uses it to synchronize its transmission of system data (suchas temperatures, pressures, or other desired information) with the clockcycle of the controller 150. This data is digitized by a processor onthe front-end circuit board 637 according to the clock signal and apre-set sequence of data type and source address (i.e. type and locationof the sensor providing the data). The front-end interface circuit board636 receives the data from the front-end board 637 and transmits thedata set to the main board 618 for use by the controller 150 inevaluation, display, and system control. Additional optical couplers canbe added between the multiple use module and single use module fortransmission of control data from the multiple use module to the singleuse module, such data including heater control signals or clamp/flowrestrictor controls.

IV. DESCRIPTION OF EXEMPLARY SYSTEM OPERATION

A. Generally

As described below, the system 600 can be configured to operate inmultiple modes such as: perfusion circuit priming mode, organstabilization mode, maintenance mode, chilling mode, andself-test/diagnostic mode. During each mode the system (vis-à-vis thecontroller 150) can be configured to operate in different manners. Forexample, as described more fully below, during the different modes ofoperation characteristics of, for example, perfusion fluid flow rates,perfusion fluid pressure, perfusion fluid temperature, etc. can vary.

Additionally, some embodiments of the system 600 can include a self-testmode in which diagnostics can be performed. For example, the system 600can automatically test circuits and sensors in the single use andmultiple use modules before the organ is instrumented on the system. Thesystem 600 can also check to ensure that the single use module isinstalled properly in the multiple use module (e.g., all connections aresecure and functioning). In the event of a failure, the system caninform the user and inhibit further operation of the system until theissue is resolved.

B. Temperature Monitoring and Control

In general, the temperature of an organ contained in the system 600 canbe controlled by circulating warmed or cooled perfusion fluidtherethrough. Thus, the perfusion fluid itself can be used to controlthe temperature of the organ without using a dedicated heater/coolerwithin the organ chamber 104.

In some embodiments of the system 600, the controller 150 can beconfigured to receive signals from one or more temperature sensors suchas temperature sensors 120, 122, 124. While these sensors are describedas being located at or near the heater 110, this is not required. Forexample, temperature sensors that measure the temperature of theperfusion fluid can be placed throughout the system 100 such as in thebranches 313, 315, in the measurement drain 2804, in the drain 2806,and/or in the reservoir 160. Additional temperature sensors can also beincluded to measure other temperature aspects of the system 600. Forexample, the system 600 can include ambient air temperature sensors thatmeasure the temperature of the environment around the system 600,temperature sensors that measure the temperature of the environmentwithin the organ chamber 104, and/or sensors that measure thetemperature of a surface and/or internal portion of the organ containedtherein.

The controller 150 can use information from the various temperaturesensors in the system 600 in order to control the temperature of theenvironment and/or perfusion fluid therein. For example, in someembodiments the controller 150 can maintain the perfusion fluid exitingthe heater at a desired temperature. In some embodiments, the controller150 can determine a temperature differential between the perfusion fluidflowing into and out of the organ. If the temperature differential islarge, the controller 150 can indirectly determine the temperature ofthe organ and adjust the temperature of the perfusion fluid flowing intothe organ to achieve the desired organ temperature. Additionally, insome embodiments the organ chamber 104 can include a heater/cooler thatheats/cools the environment within the organ chamber 104, such as aresistive heater or a thermoelectric cooler. Such a heater/cooler can becontrolled by the controller 150.

While much of the disclosure herein focuses on heating an organ to adesired temperature, this is not intended to be limiting. In someembodiments, the system 600 can include a cooling unit (not shown) inaddition to and/or instead of the heater 110. In such embodiments, thecooling unit can be used to cool the perfusion fluid and ultimately coolthe organ itself. This can be useful during, for example,post-preservation chilling procedures used with a heart, lung, kidney,and/or liver. In some embodiments, the cooling unit can be comprised ofa gas exchanger with an integrated water cooled feature, although otherconfigurations are possible.

C. Blood Flow Monitoring and Control

Many organs in the human body receive a blood supply with a single setof pressure and flow characteristics (e.g., kidney, lung). To the extentthat these organs are maintained ex vivo in an organ care system, asingle pump and a single supply line can be used to provide perfusionfluid thereto. The liver, however, is different from other organs inthat it has two blood supplies, each with different pressure and flowcharacteristics. As noted above, the liver receives approximately ⅓ ofits blood supply from the hepatic artery and approximately ⅔ of itsblood supply from the portal vein. The hepatic artery provides apulsatile blood flow at a relatively high pressure, but low flow rate.In contrast, the portal vein provides a substantially nonpulsatile bloodflow at a relatively low pressure, but high flow rate. Because of thesedifferent flow characteristics, providing perfusion fluid to an ex vivoliver can present challenges when a single pump is used. Thus, someembodiments of the organ care system 600 include a system that isconfigured to provide a dual flow of perfusion fluid in a manner thatmimics the human body. Specifically, the branch 315 of the system 100can provide perfusion fluid to the hepatic artery in a pulsatile,high-pressure, low flow manner. The branch 313 of the system 100 canprovide perfusion fluid to the portal vein in a non-pulsatile, lowpressure, high flow manner.

As noted above, the pump 106 can provide a flow of perfusion fluid at apredetermined flow rate, which can be split at the divider 105. In someembodiments, the fluid flow can be split between the hepatic artery andthe portal vein at a ratio of between 1:2 and 1:3. In some embodiments,the divider is configured such that the branch 313 uses ⅜″ tubing andthe branch 315 uses ¼″ tubing. In some embodiments, a portal vein clampcan be used to help attain this split ratio and/or can be used torestrict the resulting flow in the portal vein leg of the circuit (e.g.,branch 313) so as to create higher pressure flow in the hepatic arteryleg of the circuit (e.g., branch 315) and lower pressure flow in theparallel portal vein leg of the circuit. In some embodiments, a user canmanually adjust the portal vein clamp (e.g., such as the flow clamp 190)to effect a hepatic pressure in the acceptable range and adjust the pumpflow rate to provide an acceptable hepatic artery flow rate. Thecombination of these two adjustments (portal vein clamp and pump flowrate) can result in acceptable hepatic artery flow and pressure andcorrespondingly acceptable portal vein pressure and flow rate.

In some embodiments, the portal vein clamp can be implemented asmechanism controlled by the system, such as an electromechanical orpneumatically controlled clamp. The system can adjust the pump flow andportal vein clamp in response to pressure and flow values measured onthe hepatic artery and portal vein branches to effect pressures andflows in acceptable ranges for these paths. For example, in embodimentsthat use an automated portal vein clamp, if the controller 150 detectsthat the flow in the hepatic artery branch 315 is too low, thecontroller 150 can increase the flow rate provided by the pump 106.Likewise, if the controller detects that the pressure in the hepaticartery branch 315 is too low, the controller 150 can cause the portalvein clamp to close slightly in order to increase the pressure inhepatic artery branch 315.

In some embodiments, the controller 150 can monitor the level ofperfusion fluid in the system 600. In the event that the amount ofperfusion fluid is below recommended levels, the controller 150 canalert the user to this fact so that they may take recommended actionsuch as adjusting pump flow and/or adding additional perfusion fluid tothe system. Additionally, if the level is below a critical level, thecontroller 150 can automatically reduce the pump flow to a reduced orminimal level while alerting the user.

D. Gas Monitoring and Control

In some embodiments, the system 600 can be configured to automaticallycontrol pressure within the system by varying the flow rate of the pump106 and/or by controlling the infusion of a vasodilator. For example,one of the infusions provided by the solution pump 631 can be, or cancontain a vasodilator. When a vasodilator is administered, the perfusionfluid pressure for a given flow rate within the system 100 can drop (dueto the dilation of the vasculature in the liver). Thus, for example,reducing the infusion rate of a vasodilator can result in increasedperfusate pressure. An optimal balance can be achieved at the leastamount of vasodilator that results in adequate liver perfusion.

The system 600 can be configured to control the gas content in theperfusion fluid in such a manner that it mimics the human body.Accordingly, in some embodiments, the system 600 includes a gasexchanger (e.g., gas exchanger 114) that is configured to provide O₂and/or other desirable gases to the perfusion fluid. In principle, a gasexchanger works by facilitating the flow of a high concentration of gasto an area of low concentration of gas. In this way, the O₂ in themaintenance gas (e.g., the gas provided to the gas exchanger) can bediffused to the O₂ depleted perfusion fluid and the relatively highlevel of CO₂ in the perfusion fluid can be diffused to the maintenancegas before it is exhausted from the gas exchanger. The maintenance gasprovided to the gas exchanger can be comprised of the appropriatemixture of O₂, N₂, and CO₂, where the concentration of O₂ is higher, andthe concentration of CO₂ is lower than that in the perfusion solutionexiting a metabolically-active liver. In some instances the gas iscomprised of only O₂ and N₂.

Some embodiments of the system 600 include an oxygenation sensor (e.g.,sensor 140) that can be used to provide information about theoxygenation of the perfusion fluid. If the oxygenation level is too low,the rate of gas supplied to the gas exchanger can be increased to raisethe level of oxygen in the perfusion fluid. Likewise, if the level istoo high, the rate of gas supplied to the gas exchanger can bedecreased. Control of the gas supply to the gas exchanger can beperformed manually by the user (e.g., through the operator interfacemodule 146) and/or automatically. In an automated embodiment, thecontroller 150 can automatically increase or decrease the gas flow fromthe onboard gas supply to the gas exchanger to effect the desired changein oxygenation level.

The liver, however, can present an additional challenge providing theproper perfusion fluid gas content. Because of its inherent metabolism,the liver produces CO₂ that replaces O₂ contained in the perfusate. Insome embodiments, measuring the O₂ levels alone is not sufficient todetermine the amount of CO₂ present in the perfusion fluid. Thus, someembodiments the system 600 can be configured to separately monitor thelevel of CO₂ in the perfusion fluid to ensure that it stays within anacceptable range. In these embodiments, the gas exchanger can also beused to reduce or even eliminate CO₂ from the perfusion fluid as itpasses therethrough.

In order to determine the carbon dioxide level in the perfusate, someembodiments of the system 600 incorporate blood sample ports so that theuser can withdraw blood samples to assess the levels of carbon dioxidein the perfusate via a third party blood gas analyzer. Based on thisanalysis, the user can assign a gas flow rate into the gas exchanger inorder to effect an acceptable carbon dioxide level in the perfusate. Forexample, higher than acceptable levels of carbon dioxide can require ahigher gas flow rate to the gas exchanger to reduce the resulting levelof carbon dioxide. However, it can be advantageous to keep the gas flowto the gas exchanger as low as possible in order to maximize the life ofthe onboard gas supply—an important factor in extended transportscenarios.

Some embodiments of the system 600 can incorporate a blood gas analysissystem (not shown). In these embodiments, the blood gas analysis systemcan be configured to sample perfusion fluid flowing within the system100. For example, the blood gas analysis system can be configured totake samples of perfusion fluid at one or more locations in the system100 such as in branches 313, 315, in the measurement drain 2804, and/orin the main drain 2806. By measuring the concentration of oxygen and/orcarbon dioxide in the perfusate, the controller 150 can automaticallyincrease or decrease, as the case may be, the flow of gas to the gasexchanger to obtain the desired gas levels in the perfusion fluid.

E. Solution Delivery and Control

As noted above, some embodiments of the system 600 can include asolution pump that is configured to provide one or more solutions. Insome specific embodiments, the runtime perfusion solution comprisesthree solutions. The first solution can comprise one or more energy-richcomponent (e.g., one or more carbohydrates); and/or one or more aminoacids; and/or one or more electrolytes; and/or one or more bufferingagents (e.g., bicarbonate). In some particular embodiments, the firstsolution can comprise TPN (Clinimix E), buffering agents (e.g., sodiumbicarbonate and phosphates), heparin and insulin. The second solutioncan comprise one or more vasodilators. In some particular embodiments,the vasodilator used is Flolan®. The third solution can comprise bileacid or salts (e.g., Na Taurocholic acid salt). In some embodiments, thethree solutions are kept separate from one another and administeredseparately (e.g., using the three channels of the solution pump 631). Inother embodiments, the three solutions, optionally all aqueoussolutions, can be mixed together to form the runtime perfusionsolutions. In certain embodiments, a sufficient amount of heparin can beprovided (e.g., amount sufficient to maintain activated clotting time(ACT) for about or more than 400 seconds ACT).

V. SOLUTIONS

Exemplary solutions that can be used in the organ care system 600according to one or more embodiments are now described. Varioussolutions can be used at different times in the preservation/treatmentprocess.

A. Donor Flush

If the organ being harvested is an abdominal organ, the surgeonperforming the harvest can perform a donor flush in vivo or ex vivo toremove donor blood and/or other matter from the organ. The flush usedduring the donor flush can be an intracellular or extracellular solutionsuch as the University of Wisconsin Solution, a modified University ofWisconsin Solution, or a histidine-tryptophan-ketoglutarate (HTK)solution.

B. Initial Flush Solution

In some embodiments, after the donor flush (regardless of whether thedonor flush was done in vivo or ex vivo) and before it is placed in thepreservation chamber of the organ care system 600, an initial flushsolution can be used to flush the liver in vivo or ex vivo in order toremove the residual blood and any solution used in the donor flush. Thisflush solution is referred to herein as the initial flush solution,which is optionally a sterile solution. In some embodiments, the maincomponents of the initial flush solution can include a buffered isotonicelectrolyte solution, such as Plasmalyte, and an ti-inflammatory, suchas SoluMedrol. In some embodiments, the initial flush can be used toremove the fluid used during the donor flush. In some embodiments, themain components of the initial flush solution can include electrolytesand buffering agents. Non-limiting examples of the electrolytes includevarious salts of sodium, potassium, calcium, magnesium, chloride,hydrogen phosphate, and hydrogen carbonate. A proper combination of theelectrolytes in suitable concentrations can help maintain thephysiological osmotic pressure of the intracellular and extracellarenvironment in liver. Non-limiting examples of the buffering agentsinclude bicarbonate ions. The buffering agents in the initial flushsolution can serve to maintain the pH value inside the liver organ to beat or close to the physiological state, e.g., about 7.3 to 7.6, 7.4 to7.6, or 7.4 to 7.5. Preferably, after the liver is subjected to theinitial flush and cooled according to one more embodiments describedherein, the harvested liver can be placed into the organ care system 600according to one more embodiments.

C. Priming Solution and Additives

In certain embodiments, prior to the placement of the liver into theorgan care system 600, the organ care system 600 can be primed with apriming solution. The priming solution can be sterile and can be used toevaluate the physical integrity of the system and/or to help remove theair in the system. The composition of the priming solution can besimilar or identical to that of the runtime perfusion solution,described in more detail below. The priming solution can include certainadditives to render the system compatible with liver preservation. Forinstance, the liver regularly produces coagulation factors promotingblood coagulation. In order to prevent the blood (e.g., donor's bloodused as part of the perfusion fluid for preserving the liver on theorgan care system 600) from clotting during preservation, anti-clottingagents can be added to the priming solution as additives. Non-limitingexamples of anti-clotting agents include heparin. Heparin can beadministered throughout the preservation session to maintain ACT(activated clotting time) of ≥400 seconds, although other ACT values canbe used. Depending on the liver being maintained, the amount of heparinneeded to achieve the desired ACT can vary. In some embodiments, theheparin can be provided continuously or at intervals such as at 0, 3,and 6 hours post-instrumentation on the system 600. In certainembodiments, the organ care system 600 can be primed by a blood product(e.g., donor's blood) or synthetic blood product prior to the placementof the liver into the organ care system 600. In certain embodiments, thesystem 600 can be primed by the priming solution and/or the blood orsynthetic blood product. The system 600 can be primed by the mixture ofthe priming solution and the blood or synthetic blood product, or by thepriming solution and the blood or synthetic blood product sequentially.In some embodiments, the organ care system 600 is primed with theperfusion fluid described herein (e.g., the perfusion fluid used topreserve the organ). Alternatively or additionally, any one of thefollowing combined with either albumen or dextran can also be used:donor blood, red blood cells (RBC), or RBCs plus fresh frozen plasmaplus

Table 1 sets forth components that can be used in an exemplary primingsolution.

TABLE 1 Composition of Exemplary Priming Solution Component AmountSpecification pRBCs 1200-1500 ml ±about 10% 25% Albumin 400 ml ±about10% PlasmaLyte 700 ml ±about 10% Cefazoline or 1 g ±about 10% equivalentantibiotic (gram positive and gram negative) Cipro or equivalent 100 mg±about 10%. antibiotic (gram positive and gram negative) Solu-Medrol or500 mg ±about 10%. equivalent anti- inflammatory HCO₃ ⁻ 50 mmol ±about10%. Multivitamin 1 unit Calcium Gluconate 4.65 mEq ±about 10%. Heparin(optional) 10000 Units ±about 10%.

The exemplary priming solution can be added to the organ care system 600through the priming step S024, as more fully described with reference toFIG. 29 (described more fully below).

D. Runtime Perfusion Solution

During the preservation of the harvested liver in the organ care system600 (e.g., during transport), a perfusion fluid or perfusate, can beused to perfuse the liver and maintain the liver function at or nearphysiological conditions. In certain embodiments, the perfusion fluidcomprises a runtime perfusion solution (also referred to as amaintenance solution) and/or a blood product, e.g., donor's blood, otherindividual's compatible blood, or synthetic blood. The perfusion fluidcan be periodically/continuously infused by, for example, the solutionpump 631 in order to provide nutrients that can maintain the liverduring preservation. In some embodiments, the runtime perfusion solutionand/or the blood product are sterile.

The compositions of the runtime perfusion solution and the primingsolution are now described in more detail. According to certainembodiments, the runtime perfusion solution with particular solutes andconcentration is selected and proportioned to enable the organ tofunction at physiologic or near physiologic conditions. For example,such conditions include maintaining organ function at or near aphysiological temperature and/or preserving the liver in a state thatpermits normal cellular metabolism, such as protein synthesis, glucosestorage, lipid metabolism, and bile production. In some embodiments, thepriming solution and runtime solution can be selected to be similar oreven identical to one another.

In certain embodiments, the runtime perfusion solution is formed fromcompositions by combining components with a fluid, from moreconcentrated solutions by dilution, or from more dilute solutions byconcentration. In exemplary embodiments, suitable runtime perfusionsolutions include an energy source, and/or one or more stimulants toassist the organ in continuing its normal physiologic function prior toand during transplantation, and/or one or more amino acids selected andproportioned so that the organ continues its cellular metabolism duringperfusion. The runtime perfusion solution can include any therapeuticagents described in more detail below. Cellular metabolism includes, forexample conducting protein synthesis while functioning during perfusion.Some illustrative solutions are aqueous based, while other illustrativesolutions are non-aqueous, for example organic solvent-based,ionic-liquid-based, or fatty-acid-based.

The runtime perfusion solution can include one or more energy-richcomponents to assist the liver in conducting its normal physiologicfunction. These components can include energy rich materials that aremetabolizable, and/or components of such materials that an organ, e.g.,liver, can use to synthesize energy sources during perfusion. Exemplarysources of energy-rich molecules include, for example, one or morecarbohydrates. Examples of carbohydrates include monosaccharides,disaccharides, oligosaccharides, polysaccharides, or combinationsthereof, or precursors or metabolites thereof. While not meant to belimiting, examples of monosaccharides suitable for the solutions includeoctoses; heptoses; hexoses, such as fructose, allose, altrose, glucose,mannose, gulose, idose, galactose, and talose; pentoses such as ribose,arabinose, xylose, and lyxose; tetroses such as erythrose and threose;and trioses such as glyceraldehyde. While not meant to be limiting,examples of disaccharides suitable for the solutions include (+)-maltose(4-O-(α-D-glucopyranosyl)-α-D-glucopyranose), (+)-cellobiose(4-O-(β-D-glucopyranosyl)-D-glucopyranose), (+)-lactose(4-O-(β-D-galactopyranosyl)-β-D-glucopyranose), sucrose(2-O-(α-D-glucopyranosyl)-β-D-fructofuranoside). While not meant to belimiting, examples of polysaccharides suitable for the solutions includecellulose, starch, amylose, amylopectin, sulfomucopolysaccharides (suchas dermatane sulfate, chondroitin sulfate, sulodexide, mesoglycans,heparan sulfates, idosanes, heparins and heparinoids), dextrin, andglycogen. In some embodiments, monossacharides, disaccharides, andpolysaccharides of both aldoses, ketoses, or a combination thereof areused. One or more isomers, including enantiomers, diastereomers, and/ortautomers of monosacharides, disaccharides, and/or polysaccharides,including those described and not described herein, can be employed inthe runtime perfusion solution described herein. In some embodiments,one or more monossacharides, disaccharides, and/or polysaccharides canhave been chemically modified, for example, by derivatization and/orprotection (with protecting groups) of one or more functional groups. Incertain embodiments, carbohydrates, such as dextrose or other forms ofglucose are preferred.

Other possible energy sources include, co-enzyme A, pyruvate, flavinadenine dinucleotide (FAD), thiamine pyrophosphate chloride(co-carboxylase), β-nicotinamide adenine dinucleotide (NAD),β-nicotinamide adenine dinucleotide phosphate (NADPH), and phosphatederivatives of nucleosides, i.e. nucleotides, including mono-, di-, andtri-phosphates (e.g., UTP, GTP, GDF, and UDP), coenzymes, or otherbio-molecules having similar cellular metabolic functions, and/ormetabolites or precursors thereof. For example, phosphate derivatives ofadenosine, guanosine, thymidine (5-Me-uridine), cytidine, and uridine,as well as other naturally and chemically modified nucleosides arecontemplated.

In certain embodiments, one or more carbohydrates can be provided alongwith a phosphate source, such as a nucleotide. The carbohydrate can helpenable the organ to produce ATP or other energy sources duringperfusion. The phosphate source can be provided directly through ATP,ADP, AMP or other sources. In other illustrative embodiments, aphosphate is provided through a phosphate salt, such asglycerophosphate, sodium phosphate or other phosphate ions. A phosphatecan include any form thereof in any ionic state, including protonatedforms and forms with one or more counter ions. The energy source usedcan depend on the type of organ being perfused (e.g., adenosine can beomitted when perfusing a liver).

One of the liver's important functions is to produce bile liquid. Insome embodiments, the runtime perfusion solution comprises one or morecompounds supporting the production of bile by the liver. Non-limitingexamples of such compounds include cholesterol, primary bile acids,secondary bile acids, glycine, taurine, and bile acids (bile salts) topromote production of bile by the liver ex vivo, all of which can beused by the liver to produce bile. In some specific embodiments, thebile salt is Na Taurocholic acid salt.

Because of the liver's function as the metabolism powerhouse of thebody, it is typically in constant need of energy source and oxygen.Thus, in addition to maintaining the proper concentration of the energysource compounds in the perfusion liquid, the organ care system 600described herein can also configured to provide constant oxygen supplyto the preserved liver. In some embodiments, the oxygen is provided bydiffusing an oxygen gas flow through the perfusion liquid (e.g., in thegas exchanger 114) or the blood product to dissolve or saturate oxygenin the liquid medium, e.g., by binding oxygen to the hemoglobin in theblood product. In certain embodiments, the perfusion liquid supplied tothe liver contains O₂ in PaO₂≥200 mmHg (arterial perfusate). In certainembodiments, the perfusion liquid supplied to the liver contains lessthan PaCO₂≤40 mmHg of carbon dioxide thereby promoting and maintainingthe oxidative metabolic functions of the liver. In certain embodiments,the perfusion liquid contains less than 30 mmHg≤PACO₂ of carbon dioxidethereby maintaining the pH value in the liver to maintain its biologicalfunctions.

The runtime perfusion solution described herein can include one or moreamino acids, preferably a plurality of amino acids, to support proteinsynthesis by the organ's cells. Suitable amino acids include, forexample, any of the naturally-occurring amino acids. The amino acids canbe, in various enantiomeric or diastereomeric forms. For example,solutions can employ either D- or L-amino acids, or a combinationthereof, i.e., solutions enantioenriched in more of the D- or L-isomeror racemic solutions. Suitable amino acids can also be non-naturallyoccurring or modified amino acids, such as citrulline, ornithine,homocystein, homoserine, β-amino acids such as β-alanine, amino-caproicacid, or combinations thereof.

Certain exemplary runtime perfusion solutions include some but not allnaturally-occurring amino acids. In some embodiments, runtime perfusionsolutions include essential amino acids. For example, a runtimeperfusion solution can be prepared with one or more or all of thefollowing amino-acids: Glycine, Alanine, Arginine, Aspartic Acid,Glutamic Acid, Histidine, Isoleucine, Leucine, Methionine,Phenylalanine, Proline, Serine, Thereonine, Tryptophan, Tyrosine,Valine, and Lysine acetate.

In certain embodiments, non-essential and/or semi-essential amino acidsare not included in the runtime perfusion solution. For example, in someembodiments, asparagine, glutamine, and/or cysteine are not included. Inother embodiments, the solution contains one or more non-essentialand/or semi-essential amino acids. Accordingly, in some embodiments,asparagine, glutamine, and/or cysteine are included.

The runtime perfusion solution can also contain electrolytes,particularly calcium ions for facilitating enzymatic reactions, and/ormaintain osmotic pressure within the liver. Other electrolytes can beused, such as sodium, potassium, chloride, sulfate, magnesium and otherinorganic and organic charged species, or combinations thereof. Itshould be noted that any component provided hereunder can be provided,where valence and stability permit, in an ionic form, in a protonated orunprotonated form, in salt or free base form, or as ionic or covalentsubstituents in combination with other components that hydrolyze andmake the component available in aqueous solutions, as suitable andappropriate.

In certain embodiments, the runtime perfusion solution containsbuffering components. For example, suitable buffer systems include2-morpholinoethanesulfonic acid monohydrate (MES), cacodylic acid,H₂CO₃/NaHCO₃ (pK_(a1)), citric acid (pK_(a3)),bis(2-hydroxyethyl)-imino-tris-(hydroxymethyl)-methane (Bis-Tris),N-carbamoylmethylimidino acetic acid (ADA),3-bis[tris(hydroxymethyl)methylamino]propane (Bis-Tris Propane)(pK_(a1)), piperazine-1,4-bis(2-ethanesulfonic acid) (PIPES),N-(2-Acetamido)-2-aminoethanesulfonic acid (ACES), imidazole,N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES),3-(N-morpholino)propanesulphonic acid (MOPS), NaH₂PO₄/Na₂HPO₄ (pK_(a2)),N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES),N-(2-hydroxyethyl)-piperazine-N′-2-ethanesulfonic acid (HEPES),N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonic acid)(HEPPSO), triethanolamine, N-[tris(hydroxymethyl)methyl]glycine(Tricine), tris hydroxymethylaminoethane (Tris), glycineamide,N,N-bis(2-hydroxyethyl) glycine (Bicine), glycylglycine (pK_(a2)),N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TAPS), or acombination thereof. In some embodiments, the solutions contain sodiumbicarbonate, potassium phosphate, or TRIS buffer.

The runtime perfusion solution can include other components to helpmaintain the liver and protect it against ischemia, reperfusion injuryand other ill effects during perfusion. In certain exemplary embodimentsthese components can include hormones (e.g., insulin), vitamins (e.g.,an adult multi-vitamin, such as multi-vitamin MVI-Adult), and/orsteroids (e.g., dexamethasone and SoluMedrol).

In another aspect, a blood product can be provided with the runtimeperfusion solution to support the liver during preservation. Exemplarysuitable blood products can include whole blood, and/or one or morecomponents thereof such as blood serum, plasma, albumin, and red bloodcells. In embodiments where whole blood is used, the blood can be passedthrough a leukocyte and platelet depleting filter to reduce pyrogens,antibodies and/or other items that can cause inflammation in the organ.Thus, in some embodiments, the perfusion fluid employs whole blood thathas been at least partially depleted of leukocytes and/or whole bloodthat has been at least partially depleted of platelets.

The perfusion fluid comprising the blood product and the runtimeperfusion solution can be provided at a physiological temperature andmaintained thereabout throughout perfusion and recirculation. As usedherein, “physiological temperature” is referred to as temperaturesbetween about 25° C. and about 37° C., for example, between about 30° C.and about 37° C., such as between about 34° C. and about 37° C.

Other components or additives can be added to the runtime perfusionsolution, including, for example, adenosine, magnesium, phosphate,calcium, and/or sources thereof. In some embodiments, additionalcomponents are provided to assist the liver in conducting its metabolismduring perfusion. These components include, for example, forms ofadenosine, which can be used for ATP synthesis, for maintainingendothelial function, and/or for attenuating ischemia and/or reperfusioninjury. Components can also include other nucleosides, such asguanosine, thymidine (5-Me-uridine), cytidine, and uridine, as well asother naturally and chemically modified nucleosides includingnucleotides thereof. According to some embodiments, a magnesium ionsource is provided with a phosphate source, and in certain embodiments,with adenosine to further enhance ATP synthesis within the cells of theperfused liver. A plurality of amino acids can also be added to supportprotein synthesis by the liver cells. Applicable amino acids caninclude, for example, any of the naturally-occurring amino acids, aswell as those mentioned above.

In some embodiments, the runtime perfusion solution further comprisesone or more vasodilators (e.g., a vasodilator can be used to increase ordecrease vascular tone and thereby the pressure within the vessel). Insome particular embodiments, the vasodilator used is Flolan® althoughother vasodilators can also be used.

Table 2 sets forth components that can be used in a runtime perfusionsolution for preserving a liver as described herein. The runtimeperfusion solution can include one or more of the components describedin Table 2.

TABLE 2 Component of Exemplary Composition for the Runtime PerfusionSolution Exemplary Concentration Ranges in Component PreservativeSolution Alanine about 1 mg/L-about 10 g/L Arginine about 1 mg/L-about10 g/L Asparagine about 1 mg/L-about 10 g/L Aspartic Acid about 1mg/L-about 10 g/L Cysteine about 1 mg/L-about 10 g/L Cystine about 1mg/L-about 10 g/L Glutamic Acid about 1 mg/L-about 10 g/L Glutamineabout 1 mg/L-about 10 g/L Glycine about 1 mg/L-about 10 g/L Histidineabout 1 mg/L-about 10 g/L Hydroxyproline about 1 mg/L-about 10 g/LIsoleucine about 1 mg/L-about 10 g/L Leucine about 1 mg/L-about 10 g/LLysine about 1 mg/L-about 10 g/L Methionine about 1 mg/L-about 10 g/LPhenylalanine about 1 mg/L-about 10 g/L Proline about 1 mg/L-about 10g/L Serine about 1 mg/L-about 10 g/L Threonine about 1 mg/L-about 10 g/LTryptophan about 1 mg/L-about 10 g/L Tyrosine about 1 mg/L-about 10 g/LValine about 1 mg/L-about 10 g/L Adenine about 1 mg/L-about 10 g/L ATPabout 10 ug/L-about 100 g/L Adenylic Acid about 10 ug/L-about 100 g/LADP about 10 ug/L-about 100 g/L AMP about 10 ug/L-about 100 g/L AscorbicAcid about 1 ug/L-about 10 g/L D-Biotin about 1 ug/L-about 10 g/LVitamin D-12 about 1 ug/L-about 10 g/L Cholesterol about 1 ug/L-about 10g/L Dextrose (Glucose) about 1 g/L-about 150 g/L Multi-vitamin Adultabout 1 mg/L-about 20 mg/L or 1 unit vial Epinephrine about 1 ug/L-about1 g/L Folic Acid about 1 ug/L-about 10 g/L Glutathione about 1ug/L-about 10 g/L Guanine about 1 ug/L-about 10 g/L Inositol about 1g/L-about 100 g/L Riboflavin about 1 ug/L-about 10 g/L Ribose about 1ug/L-about 10 g/L Thiamine about 1 mg/L-about 10 g/L Uracil about 1mg/L-about 10 g/L Calcium Chloride about 1 mg/L-about 100 g/L NaHCO₃about 1 mg/L-about 100 g/L Magnesium sulfate about 1 mg/L-about 100 g/LPotassium chloride about 1 mg/L-about 100 g/L Sodium glycerophosphateabout 1 mg/L-about 100 g/L Sodium Chloride about 1 mg/L-about 100 g/LSodium Phosphate about 1 mg/L-about 100 g/L Insulin about 1 IU-about 150IU Serum albumin about 1 g/L-about 100 g/L Pyruvate about 1 mg/L-about100 g/L Coenzyme A about 1 ug/L-about 10 g/L Serum about 1 ml/L-about100 ml/L Heparin about 500 U/L-about 1500 U/L Solumedrol about 200mg/L-about 500 mg/L Dexamethasone about 1 mg/L-about 1 g/L FAD about 1ug/L-about 10 g/L NADP about 1 ug/L-about 10 g/L guanosine about 1mg/L-about 10 g/L GTP about 10 ug/L-about 100 g/L GDP about 10ug/L-about 100 g/L GMP about 10 ug/L-about 100 g/L

Table 3 sets forth components that can be used in an exemplary runtimeperfusion solution. The amounts provided in Table 3 describe preferredamounts relative to other components in the table and can be scaled toprovide compositions of sufficient quantity. In some embodiments, theamounts listed in Table 3 can vary by ±about 10% and still be used inthe solutions described herein.

TABLE 3 Components of Exemplary Runtime Perfusion Solution ComponentAmount Calcium Chloride dihydrate About 2100 mg-About 2600 mg GlycineAbout 315 mg-About 385 mg L-Alanine About 150 mg-About 200 mg L-ArginineAbout 600 mg-About 800 mg L-Aspartic Acid About 220 mg-About 270 mgL-Glutamic Acid About 230 mg-About 290 mg L-Histidine About 200 mg-About250 mg L-Isoleucine About 100 mg about 130 mg L-Leucine About 300mg-About 380 mg L-Methionine About 50 mg-About 65 mg L-PhenylalanineAbout 45 mg-About 60 mg L-Proline About 110 mg-About 140 mg L-SerineAbout 80 mg-About 105 mg L-Thereonine About 60 mg-About 80 mgL-Tryptophan About 30 mg-About 40 mg L-Tyrosine About 80 mg-About 110 mgL-Valine About 150 mg-About 190 mg Lysine Acetate About 200 mg-About 250mg Magnesium Sulfate Heptahydrate About 350 mg-About 450 mg PotassiumChloride About 15 mg-About 25 mg Sodium Chloride About 1500 mg-About2000 mg Dextrose About 25 gm-About 120 gm Epinephrine About 0.25mg-About 1.0 mg Insulin About 75 Units-About 150 Units MVI-Adult 1 unitvial SoluMedrol About 200 mg-500 mg Sodium Bicarbonate About 10-25 mEq

In the exemplary embodiment of a runtime perfusion solution, thecomponents in Table 3 can be combined in the relative amounts listedtherein per about 1 L of aqueous fluid to form the runtime perfusionsolution. In some embodiments, the quantity of aqueous fluid in theruntime perfusion solution can vary ±about 10%. The pH of the runtimeperfusion solution can be adjusted to be between about 7.0 and about8.0, for example about 7.3 and about 7.6. The runtime perfusion solutioncan be sterilized, for example by autoclaving, to provide for improvedpurity.

Table 4 sets forth another exemplary runtime perfusion solution,comprising a tissue culture media having the components identified inTable 4 and combined with an aqueous fluid, which can be used in theperfusion fluid as described herein. The amounts of components listed inTable 4 are relative to each other and to the quantity of aqueoussolution used. In some embodiments, about 500 mL of aqueous fluid isused. In some embodiments, the quantity of aqueous solution can vary±about 10%. The component amounts and the quantity of aqueous solutioncan be scaled as appropriate for use. The pH of the runtime perfusionsolution, in this embodiment, can be adjusted to be about 7.0 to about8.0, for example about 7.3 to about 7.6.

TABLE 4 Composition of Another Exemplary Runtime Perfusion Solution(about 500 mL aqueous solution) Tissue Culture Component AmountSpecification Calcium Chloride dihydrate 2400 mg ±about 10% Glycine 350mg ±about 10% L-Alanine 174 mg ±about 10% L-Arginine 700 mg ±about 10%L-Aspartic Acid 245 mg ±about 10% L-Glutamic Acid 258 mg ±about 10%L-Histidine 225 mg ±about 10% L-Isoleucine 115.5 mg ±about 10% L-Leucine343 mg ±about 10% L-Methionine 59 mg ±about 10% L-Phenylalanine 52 mg±about 10% L-Proline 126 mg ±about 10% L-Serine 93 mg ±about 10%L-Thereonine 70 mg ±about 10% L-Tryptophan 35 mg ±about 10% L-Tyrosine92 mg ±about 10% L-Valine 171.5 mg ±about 10% Lysine Acetate 225 mg±about 10% Magnesium Sulfate Heptahydrate 400 mg ±about 10% PotassiumChloride 20 mg ±about 10% Sodium Chloride 1750 mg ±about 10%

Since amino acids are the building blocks of proteins, the uniquecharacteristics of each amino acid impart certain important propertieson a protein such as the ability to provide structure and to catalyzebiochemical reactions. The selection and concentrations of the aminoacids provided in the runtime perfusion solutions can provide support ofnormal physiologic functions such as metabolism of sugars to provide orstore energy, regulation of protein metabolism, transport of minerals,synthesis of nucleic acids (DNA and RNA), regulation of blood sugar andsupport of electrical activity, in addition to providing proteinstructure. Additionally, the concentrations of specific amino acidsfound in the runtime perfusion solution can be used to predictablystabilize the pH of the runtime perfusion solution.

In certain embodiments, in order to prevent the blood used as part ofthe perfusion fluid for preserving the liver on the organ care system600 from clotting during preservation, anti-clotting agents can be addedto the runtime perfusion solution as additives. Non-limiting examples ofanti-clotting agents include heparin. In some embodiments, heparin canbe included in a sufficient amount to prevent clotting for 500-600seconds, although other times are possible.

In certain embodiments, the runtime perfusion solution includes aplurality of amino acids. In certain embodiments, the runtime perfusionsolution includes electrolytes, such as calcium and magnesium.

In one embodiment, a runtime perfusion solution includes one or moreamino acids, and one or more carbohydrates, such as glucose or dextrose.The runtime perfusion solution can also have additives, such as thosedescribed herein, administered at the point of use just prior toinfusion into the liver perfusion system. For example, additionaladditives that can be included with the solution or added at the pointof use by the user include hormones and steroids, such as dexamethasoneand insulin, as well as vitamins, such as an adult multi-vitamin, forexample adult multivitamins for infusion, such as MVI-Adult. Additionalsmall molecules and large bio-molecules can also be included with theruntime perfusion solution or added at the point of use by the user,including therapeutics and/or components typically associated with bloodor blood plasma, such as albumin.

In some embodiments, therapeutics can be added either before or duringperfusion of the liver. The therapeutics can also be added directly tothe system independently from the runtime perfusion solution, before orduring perfusion of the organ.

With further reference to Table 3 or 4, certain components used in theexemplary runtime perfusion solution are molecules, such as smallorganic molecules or large bio-molecules, that would be inactivated, forexample through decomposition or denaturing, if passed throughsterilization. Thus, these components can be prepared separately fromthe remaining components of the runtime perfusion solution. The separatepreparation involves separately purifying each component through knowntechniques. The remaining components of the runtime perfusion solutionare sterilized, for example through an autoclave, then combined with thebiological components.

Table 5 lists certain biological components that can be separatelypurified and added to the solutions (runtime perfusion solution and/orpriming solution) described herein after sterilization, according tothis two-step process. These additional or supplemental components canbe added to runtime perfusion solution, the priming solution or acombination thereof individually, in various combinations, all at onceas a composition, or as a combined solution. For example, in certainembodiments, the insulin, and MVI-Adult, listed in Table 5, are added tothe runtime perfusion solution. In another example, the SoluMedrol andthe sodium bicarbonate, listed in Table 5, are added to the primingsolution. The additional components can also be combined in one or morecombinations or all together and placed in solution before being addedto runtime perfusion solution, and/or the priming solution. In someembodiments, the additional components are added directly to theperfusion fluid. The component amounts listed in Table 5 are relative toeach other and/or to the amounts of components listed in one or more ofTables 1-4 as well as the amount of aqueous solution used in preparingthe runtime perfusion solution, and/or the priming solution and can bescaled as appropriate for the amount of solution required.

TABLE 5 Exemplary Biological Components Added to Solutions Prior to UseComponent Amount Type Specification Insulin about 100 Units Hormone±about 10% MVI-Adult 1 mL unit vial Vitamin ±about 10% SoluMedrol About250 mg Steroid ±about 10% Sodium Bicarbonate About 20 mEq Buffer ±about10%

In one embodiment, a composition for use in a runtime perfusion solutionis provided comprising one or more carbohydrates, one or more organstimulants, and a plurality of amino acids. The composition can alsoinclude other substances, such as those used in solutions describedherein.

In another embodiment, a system for perfusing a liver, is providedcomprising a liver and a substantially cell-free composition, comprisingone or more carbohydrates, one or more organ stimulants, and a pluralityof amino acids. The substantially cell-free composition can includesystems that are substantially free from cellular matter; in particular,systems that are not derived from cells. For example, substantiallycell-free composition can include compositions and solutions preparedfrom non-cellular sources.

In another aspect, the runtime perfusion solution and/or the primingsolution can be provided in the form of a kit that includes one or moreorgan maintenance solutions. An exemplary runtime perfusion solution caninclude components identified above in one or more fluid solutions foruse in a liver perfusion fluid. In certain embodiments, the runtimeperfusion solution can include multiple solutions which, in variouscombinations, provide the runtime perfusion solution. Alternatively, thekit can include dry components that can be regenerated in a fluid toform one or more runtime perfusion solution or priming solution. The kitcan also comprise components from the runtime perfusion solution orpriming solution in one or more concentrated solutions which, ondilution, provide a preservation, nutritional, and/or supplementalsolution as described herein. The kit can also include a primingsolution.

In certain embodiments, the kit is provided in a single package, whereinthe kit includes one or more solutions (or components necessary toformulate the one or more solutions by mixing with an appropriatefluid), and instructions for sterilization, flow and temperature controlduring perfusion and use and other information necessary or appropriateto apply the kit to organ perfusion. In certain embodiments, a kit isprovided with only a single runtime perfusion solution (or set of drycomponents for use in a solution upon mixing with an appropriate fluid),and along with a set of instructions and other information or materialsnecessary or useful to operate the runtime perfusion solution or primingsolution.

In certain embodiments, the runtime perfusion solution is a singularsolution. In other embodiments, the runtime perfusion solution caninclude a main runtime perfusion solution and one or more nutritionalsupplement solutions. The nutritional supplement solution can containany compound or biological component suitable for the runtime perfusiondescribe above. For instance, the nutritional supplement solution cancontain one or more components illustrated in Tables 1-5 above.Additionally, Table 6 sets forth components that are used in anexemplary nutritional supplement solution. In some embodiments, thenutritional solution further includes sodium glycerol phosphate. Theamount of components in Table 6 is relative to the amount of aqueoussolvent employed in the solution (about 500 mL) and may be scaled asappropriate. In some embodiments, the quantity of aqueous solvent varies±about 10%. In these embodiments when a main runtime solution and one ormore nutritional solutions are used, these solutions can be separatelyconnected to the circulation system of the organ care system 600 andcontrol separately. Thus, when one or more components in a nutritionalsolution need to be adjusted, the operator may remake this particularnutritional solution with different concentration for these componentsor adjust only the flow rate and/or pressure for this nutritionalsolution without affecting the flow rate and/or pressure for the mainruntime perfusion solution and other nutritional solutions.

TABLE 6 Components of Exemplary Nutritional Solution (about 500 mL)Component Amount Specification Dextrose 40 g. ±about 10%.

In one embodiment, the runtime perfusion solution and the primingsolution have the identical composition which is described in any one ofTables 1-6 or a combination thereof.

In some embodiments, the perfusion liquid comprises 1200-1500 ml ofpRBCs, 400 ml of 25% Albumin, 700 ml of PlasmaLyte, antibiotic (grampositive and gram negative) 1 g Cefazoline (or equivalent antibiotic)and 100 mg Cipro (or equivalent antibiotic), 500 mg of Solu-Medrol (orequivalent anti-inflammatory), 50 mmol Hco3, multivitamin, and 10000unit of Heparin administered at 3 hr and 6 hr PT.

In certain specific embodiments, the perfusion fluid comprises the liverdonor's blood, or packed red blood cells (RBCs), or packed RBCs withfresh frozen plasma, and the runtime perfusion solution containing oneor more components selected form the group consisting of human albuminor dextran. In certain specific embodiments, the perfusion fluidcomprises the liver donor's blood, or packed RBCs or packed RBCs withfresh frozen plasma, and the runtime perfusion solution containing oneor more components selected form the group consisting of human albumin,dextran, and one or more electrolyte.

E. Final-Flush Solution

After the suitable recipient of the liver transplant is identified andbefore the liver is removed from the organ care system 600, the liverorgan can be subjected to another flush process by a flush solution.This flush solution has the similar function as the initial flushsolution, which is to remove the residual blood therein and stabilizethe liver. This flush solution is referred to herein as the final flushsolution. In some embodiments, the final flush solution has similar oridentical compositions as the initial flush solution described above.The main components of the final flush solution can include electrolytes(e.g., plasmalyte) and buffering agents described herein. In certainembodiments, one or more commercially-available preservation solutionsused in hypothermal organ transplant are used as the final flushsolution. After the liver is subjected to the final flush and cooledaccording to one more embodiments described herein, the liver can beremoved from the organ care system 600 for implantation into arecipient.

VI. METHODS

Exemplary methods to use the organ care system 600 disclosed herein arenow described in more detail. FIG. 29 is a flow diagram 5000 depictingexemplary and non-limiting methodologies for harvesting the donor liverand cannulating it into the organ care system 600 described herein. Theprocess 5000 shown in FIG. 29 is exemplary only and can be modified. Forexample, the stages described therein can be altered, changed,rearranged, and/or omitted.

A. Harvesting Organ

As shown in FIG. 29, the process of obtaining and preparing liver forcannulation and transport can begin by providing a suitable liver donor(Stage 5004). The system 600 can be brought to a donor location,whereupon the process of receiving and preparing the donor liver forcannulation and preservation can proceed down pathways 5006 and 5008.The pathway 5006 principally involves preparing the donor liver forpreservation, while the pathway 5008 principally involves preparing thesystem to receive and preserved the liver, and then transport the livervia the organ care system 600 to the recipient site.

As shown in FIG. 29, the first pathway 5006 can include exsanguinatingthe donor blood (Stage 5010), explanting the liver (Stage 5014),flushing the liver with initial flush solution (Stage 5016), andpreparing and cooling the liver for the system (Stage 5018). Inparticular, in the exsanguination stage 5010, the donor's blood can bepartially and/or wholly removed and set aside so it can be used to asthe blood product in the perfusion liquid to perfuse the liver duringpreservation on the system. This stage can be performed by inserting acatheter into either the arterial or venous vasculature of the donor toallow the donor's blood to flow out of the donor and be collected into ablood collection bag. The donor's blood is allowed to flow out until thenecessary amount of blood is collected, typically 1.0-2.5 liters,whereupon the catheter is removed. The blood extracted throughexsanguination is then optionally filtered and added to a fluidreservoir of the system in preparation for use with the system.Alternatively, the blood can be exsanguinated from the donor andfiltered for leukocytes and platelets in a single step that uses anapparatus having a filter integrated with the cannula and bloodcollection bag. An example of such a filter is a Pall BC2B filter.Alternatively, a blood product can be used instead of the donor's bloodin the perfusion liquid (not shown in FIG. 29).

After the donor's blood is exsanguinated, the donor liver can beharvested (Stage 5014). Any standard liver harvesting method known inthe art can be used. During liver harvesting, the liver vesselsincluding hepatic artery, portal vein, inferior vena cava (IVC), andbile duct are prepared properly and severed, with sufficient vessellength remained for cannulation (e.g., standard practice, suitable forhuman or animal transplant). In certain embodiments, the gall bladder isremoved during the liver harvesting and care is taken to preserve thecommon bile duct intact to maintain stable bile fluid flow during theliver preservation. After the liver is removed in hospital settings, itis often flushed (e.g., donor flush) or placed in saline solutions. Instage 5016, the harvested liver can then be flushed by an initial flushsolution to remove any residual blood and/or donor flush solution toimprove the stability of the liver. An exemplary composition of theinitial flush solution is described above in detail.

After the liver is harvested and prior to its placement on the organcare system 600, the liver can be cooled down (Stage 5018) to reduce orhalt its metabolic functions to avoid damage to the liver whichotherwise can occur during transportation or placement of the liver intothe organ care system 600. In certain embodiments, the liver is cooledto about 4° C. to 10° C., 5° C. to 9° C., 5° C. to 8° C., 4° C., 5° C.,6° C., 7° C., 8° C., 9° C., or 10° C., or a temperature within any rangebounded by the value described herein. The liver can be cooled by ice orrefrigeration. Other temperature ranges below 4° C. and above 10° C. arealso possible. Alternatively, the initial flush solution can be cooledfirst and then used to flush the liver to cool the liver. Thus, in thesealternative embodiments, Stages 5016 and 5018 can be performedsimultaneously. Once the liver is prepared and cooled to a propertemperature, it can be ready to be placed onto the liver care system600.

With continued reference to FIG. 29, during the preparation of the livervia path 5006, the system can be prepared through the stages of path5008 so it is primed and waiting to receive the liver for cannulationand preservation as soon as the liver is prepared and cooled. By quicklytransferring the liver from the donor to the system, and subsequentlyperfusing the liver with the perfusion fluid, a medical operator canminimize the amount of time the liver is deprived of oxygen and othernutrients, and thus reduce ischemia and other ill effects that ariseduring current organ care techniques. In certain embodiments, the amountof time between infusing the liver with the initial flush solution andbeginning flow of the perfusion fluid through the liver via the organcare system 600 is less than about 15 minutes. In other illustrativeembodiments, the between-time is less than about ½ hour, less than about1 hour, less than about 2 hours, or even less than about 3 hours.Similarly, the time between transplanting the liver into the organ caresystem 600 and bringing the liver to a near physiological temperature(e.g., between about 34° C. and about 37° C.) can occurs within a briefperiod of time so as to reduce ischemia within the liver tissues. Insome illustrative embodiments, the period of time is less than about 5minutes, while in other applications it can be less than about ½ hour,less than about 1 hour, less than about 2 hours, or even less than about3 hours. Stated differently, when the cooled liver is first placed intothe organ care system 600, the temperature of the liver can gradually beraised to the desired temperature over a predetermined amount of time toreduce any potential damage that could result of a sudden temperaturechange.

As shown in FIG. 29, the system can be prepared in pathway 5008 througha series of stages, which include preparing the single use module (stage5022), priming the system with priming solution (stage 5024), filteringthe blood from the donor and adding it to the system, e.g., at areservoir of the system (stage 5012), optionally priming the system withblood and/or perfusion fluids, and connecting the liver into the system(stage 5020). In particular, the step S022 of preparing the single usemodule includes assembling the disposable single use module describedherein (e.g., single use module 634). After the single use module isassembled, or provided in the appropriate assembly, it is then insertedinto and connected to the multiple use module (e.g., multiple use module650) through the process described herein.

Specifically, in stage 5024, the liver care system 600 can be firstprimed with a priming solution, the composition of which is describedmore fully above. In certain embodiments, to aid in priming, the systemcan provide an organ bypass conduit installed into the organ chamberassembly. For example, in certain specific embodiments, the bypassconduit includes three segments attached to the hepatic arterycannulation interface, the portal vein cannulation interface, and theinferior vena cava (IVC) cannulation interface (if present). Using thebypass conduit attached/cannulated into the liver chamber assembly, anoperator can cause the system to circulate the perfusion fluid throughall of the paths used during actual operation. This can enable thesystem to be thoroughly tested and primed prior to cannulating the liverinto place.

In stage 5012, blood from the donor can be filtered and added to thesystem, e.g., in the reservoir 160. The filtering process can helpreduce the inflammatory process through the complete or partial removalof leukocytes and platelets. Additionally, the donor blood can be usedto optionally prime the system as described above and/or mixed with oneor more priming solution or runtime perfusion solution to further primethe system as described above. Additionally, the blood and the run timeperfusion solution can be mixed together to form the perfusion fluidused later for infusing and preserving the liver. In stage 5026, thesystem can be primed with the blood and/or the perfusion fluid byactivating the pump and by pumping the blood and/or the perfusion fluidthrough the system with the bypass conduit (described above) in place.As the perfusion fluid circulates through the system in priming stage5026, it can optionally be warmed to the desired temperature (e.g.,normothermic) as it passes through a heater assembly of the system.Thus, prior to cannulating the harvested liver, the system can be primedby circulating the priming solution, exsanguinated donor blood, and/orthe mixture of the two (e.g., the perfusion fluid) through the system toheat, oxygenate and/or filter it. Nutrients, preservatives, and/or othertherapeutics can also be provided during priming by addition of thecomponents to the priming solution. During priming, various parameterscan also be initialized and calibrated via the operator interface duringpriming. Once primed and running appropriately, the pump flow can bereduced or cycled off, the bypass conduit can be removed from the organchamber assembly, and the liver can then be cannulated into the organchamber assembly.

1. Cannulation

In stage 5020, the liver, while cooled as described above, can becannulated and placed onto the organ care system 600. During liverpreservation, the perfusion fluid can flow into the liver through thehepatic artery and portal vein and flow out of the liver through theinferior vena cava (IVC). Thus, the hepatic artery, inferior vena cava(IVC), and portal vein can be correspondingly cannulated and connectedwith the relevant flow path of the liver care system 600 to ensureproper perfusion through the liver (as described above). In someembodiments, the IVC is not cannulated and free drains. The bile ductcan also be cannulated as well and connected to a reservoir to collectthe bile produced by the liver (e.g., bile bag 187).

The system 600 described herein can be designed to be compatible withthe human hepatic artery anatomy. In the majority of the patients, thehepatic artery is the only major artery of the liver and thus the organcare system 600 can a single-port cannula to be connected with thehepatic artery. In certain cases (i.e., about 10-20% of the patientpopulation with genetic difference), however, the donor of the liveralso has an accessory hepatic artery in addition to the main hepaticartery. Thus, in certain embodiments, the liver care system 600 providesa dual-port cannula configuration (e.g., cannula 2642) so that both themain and accessory hepatic arteries can be cannulated and connected tothe same perfusion fluid flow path. In certain specific embodiments, thedual-port cannula has a Y shape. Any other suitable shapes or designsfor the dual-port cannula are contemplated.

In certain embodiments, the cannula can be designed to be straight toreduce unnecessary flow pressure drop along the cannula flow path. Inother embodiments, the cannula can be designed to be curved or angled asrequired by the shape, size, or geometry of the organ care system 600'sother components. In some specific embodiments, the cannula is designedwith a proper shape, e.g., straight, angled, or a combination thereof,so that the overall flow pressure within the cannula is maintained at adesired level that mimics physiologic conditions.

2. Instrumentation

The liver can then be instrumented on the organ care system 600 (Stage5020) and more specifically, in the organ chamber 104. Care should betaken to avoid excessive movement of the liver during instrumentation toreduce injuries to the liver. As described above in greater detail, theliver chamber can be specially designed to maintain the liver in astable position that reduces its movement.

B. Preservation/transport

1. Controlled Early Perfusion and Rewarming

In certain embodiments, once the liver is instrumented on the organ caresystem 600 with proper cannulation of the vessels, the liver can besubjected to an early perfusion and/or rewarm process to restore theliver to a normothermic temperature (34-37° C.) (Stage 5021). In someembodiments, the organ chamber can contain heating circuit to warm thepreviously cooled liver to normothermic temperature gradually over apredetermined amount of time. In other embodiments, the initialperfusion fluid (for early perfusion) can be heated to close to or tothe normothermic temperature (e.g., 34-37° C.) and perfuse and warm theliver at the same time. As described herein, the liver preserved on theorgan care system 600 can be kept at conditions near to physiologicalstate, which includes normothermic temperatures, to maintain the liver'snormal biological functions.

After the liver is instrumented onto the system and warmed tonormothermic temperature, the pump within the organ care system 600(e.g., pump 106) can be adjusted to pump perfusion fluid through theliver, e.g., into the hepatic artery and portal vein. The perfusionfluid exiting from the IVC (or hepatic veins, depending on how the liverwas harvested) can be collected and subjected to various treatmentsincluding re-oxygenation and carbon dioxide removal. Various nutrientscan be added to the spent perfusion fluid to increase the nutrientconcentrations to required value for recirculation.

In some embodiments, during the liver perfusion on the organ care system600, the in-flow pressures within the hepatic artery and the portal veinare carefully controlled to ensure the proper delivery of nutrients tothe liver to maintain its functions. In some embodiments, the flowpressure within the hepatic artery can be, for example, 50-120 mmHg andthe flow pressure in the portal vein can be 5-15 mmHg, althoughpressures outside these ranges are possible such as 1, 2, 20, 25, 30,35, 40, 45, 50, 60, 70, 80, 90, 100, 110, 120 mmHg, or a pressure in anyrange bounded by the values noted here. In some embodiments, the flowrate within the hepatic artery and the portal vein can be maintained atabout or more than 0.25-1.0 L/min, and 0.75-2.0 L/min, respectively, orat any range bounded by any of the values noted here. In someembodiments, the flow rate within the hepatic artery and the portal veincan be maintained at about 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55,0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.10, 1.20, 1.30,1.40, 1.50, 1.60, 1.70, 1.80, 1.90, 2.1, 2.2, 2.3, 2.4, 2.5 L/min or arate in any range bounded by the values noted here.

In some embodiments, the fluid flow, e.g., flow rate and/or flowpressure, within the organ care system 600 and hepatic artery and theportal vein can be controlled chemically and/or mechanically. Themechanical or the chemical control of the flow can be achievedautomatically or manually.

2. Manual/automatic control

The mechanical control of the fluid flow within the organ care system600 and hepatic artery and the portal vein is first described. In someembodiments, the flow pressure or rate within the flow path of the organcare system 600 can be measured by pressure sensors or rate sensorsbuilt in the flow path or in other locations of the systems. Similarly,pressure or rate sensors can be located in the cannulas for the hepaticartery and/or the portal vein, or in the connectors connecting thecannulas to these vessels. The pressure or rate sensors can provide theoperator with readings regarding the flow within the flow path and/orwithin the hepatic artery and/or the portal vein. Any other pressuremonitoring methods or techniques known in the art are contemplated. Ifthe pressure or rate reading is deviating from the desired values, theoperator can manually adjust the flow pump to increase or decrease thepumping pressure and, thereby, the flow rate for the perfusion fluid.Alternatively, the organ care system 600 can contain a flow controlmodule which has a programmable desired value for flow rate and/or flowpressure and automatically adjusts the pumping pressure of the perfusionfluid and thereby also adjusting the flow rate when the flow pressureand/or rate are deviating from the desired values. Manual and/orautomatic control is described more fully above.

3. Chemical Control

In other embodiments, the pressure and/or fluid flow within the organcare system 600 and hepatic artery and the portal vein can be controlledchemically. In some specific embodiments, the pressure can be controlledor increased by using one or more vasodilators (e.g., a vasodilator canbe used to increase or decrease vascular tone and thereby the pressurewithin the vessel). Vasodilation refers to the widening of blood vesselsresulting from relaxation of smooth muscle cells within the vesselwalls. When blood vessels dilate, the flow of perfusion fluid isincreased due to a decrease in vascular resistance. Any vasodilatorsknown in the art can be used to dilate the hepatic artery and/or theportal vein to increase the fluid flow rate therein. In some particularembodiments, the vasodilator used is Flolan®. In particular, when thefluid flow is insufficient as indicated by low flow pressure or rate,and/or by any of the liver-viability evaluation techniques described ingreater detail below, the operator can manually add vasodilator into thesystem's flow module or to the perfusion fluid to increase the fluidflow rate. Alternatively, the organ care system 600 can contain a flowcontrol module which automatically adds one more vasodilators into theflow path or perfusion fluid to increase the flow rate. The amount ofthe vasodilator provided can be between, for example, 1-100micrograms/hr, and more specifically between 1-5 micrograms/hr. Theseranges are exemplary only and any range falling within 0-100 microgramsan hour can be used.

Some embodiments of the foregoing can be adapted for use with a liverthat is being preserved in the system 600. For example, in thisembodiment, an algorithm can be used to allow closed loop control of thehepatic artery pressure (HAP). The algorithm used can be aproportional-integral-derivative controller (PID controller). A PIDcontroller can calculate how far away the HAP is from the desired setpoint and attempt to minimize the error by increasing or decreasing thevasodilator (e.g., Flolan®) flow rate.

Accordingly, in some embodiments, the controller 150 (or other part ofthe system) can determine the error (e.g., how far the HAP is from theuser set-point) and adjust the vasodilator flow rate in an attempt tomake the error 0. In embodiments where the algorithm runs once a secondthe adjustments can be very small. Small, frequent adjustments can helpto stabilize the control by ensuring that any noise in the system doesnot result in dramatic changes in vasodilator flow rate. The algorithmcan be trying to get the HAP to the user set point. This means that whenthe HAP is above the set point the algorithm can increase thevasodilator solution flow rate until the HAP reaches the user set point.If the HAP is below the user set point the algorithm can decrease thevasodilator solution flow rate until the HAP reaches the user set point.

In some embodiments, the PID control algorithm does not decrease thevasodilator flow rate until it has gone under the set point. This canresult in undershooting the target pressure. To help offset this, someembodiments can use a virtual set point, which is +3 mmHg (or othervalue) above the user set point. This can be user definable orhard-programmed. When the HAP is higher than 7 mmHg above the user setpoint the software can enable the virtual set point and attempt toregulate the HAP to +3 mmHg above the user set point. This can allow forsome undershoot of the virtual set point. Once the HAP has stabilized atthe virtual set point the software can then regulate the HAP to the userset point. This approach can help “catch” the HAP as it is fallingwithout incurring as dramatic of an undershoot.

Referring to FIG. 28, a graphical representation of the foregoing isshown with respect to ascending aortic pressure in a heart system. InFIG. 28, an exemplary graph 9500 of the foregoing is shown. The imageshows the AOP (e.g., 9505) coming down to a virtual set point (9510),undershooting the virtual set point and then coming down softly on theuser set point (50 mmHg).

Because some embodiments use a drug to control the HAP it can bebeneficial to ensure that the system is not flooding the liver withvasodilator when it is not needed. To accomplish this, the system cananalyze how far the HAP is from the set point and when the HAP is abovethe set point, the system (e.g., the solution pump 631) can addvasodilator at the standard rate. If the HAP is below the set point, thesystem 600 can decrease the flow rate 4 times faster than if it wereadding vasodilator. This can help the system stay just above the HAP setpoint (e.g., about +0.5 to +1 mmHg) in the “active management” area aswell as potentially helping minimize undershoot but decreasingvasodilator rate faster.

While the foregoing description has focused on the liver, the sametechnique can be adapted for use with the heart by substituting AOP forthe HAP.

4. Assessment

During stages 5028 and 5030 the operator can evaluate the liverfunctions to determine liver viability for transplant (then-current orlikely future viability). Illustratively, step 5028 involves evaluatingliver functions by using any of the evaluation techniques described inmore detail below. For instance, the operator can monitor the fluidflows, pressures, and temperatures of the system while the liver iscannulated. The operator can also monitor one or more liver functionbiomarkers to assess the liver status. During the evaluation step 5030,based on the data and other information obtained during testing 5028,the operator can determine whether and how to adjust the systemproperties (e.g., fluid flows, pressures, nutrient concentrations,oxygen concentrations, and temperatures), and whether to provideadditional modes of treatment to the liver (e.g., surgeries, medicationsas described in more detail below). The operator can make any suchadjustments in step 5032, can then repeat steps 5028 and 5030 to re-testand re-evaluate the liver and the system. In certain embodiments, theoperator can also opt to perform surgical, therapeutic or otherprocedures on liver (described in more detail below) during theadjustment step 5032 (or at other times). For example, the operator canconduct an evaluation of the liver functions, such as for example,performing an ultrasound or other imaging test on the liver, measuringarterial and venous blood gas levels and other evaluative tests.

Thus, after or while the liver is preserved on the system, the operatorcan perform surgery on the liver or provide therapeutic or othertreatment, such as immunosuppressive treatments, chemotherapy, genetictesting and therapies, or irradiation therapy. Because the system allowsthe liver to be perfused under near physiological temperature, fluidflow rate, and oxygen saturation levels, the liver can be maintained fora long period of time (e.g., for a period of at least 3 days or more,greater than at least 1 week, at least 3 weeks, or a month or more) toallow for repeated evaluation and treatment.

In some embodiments, the system allows a medical operator to evaluatethe liver for compatibility with an intended recipient by identifyingsuitable recipient (Step 5034). For example, the operator can perform aHuman Leukocyte Antigen (HLA) matching test on the liver while the liveris cannulated to the system. Such tests can require 12 hours or longerand are performed to ensure compatibility of the liver with the intendedrecipient. The preservation of a liver using the system described hereincan allow for preservation times in excess of the time needed tocomplete an HLA match, potentially resulting in improved post-transplantoutcomes. In the HLA matching test example, the HLA test can beperformed on the liver while a preservation solution is pumping into theliver. Any other matching test known in the art is contemplated.

According to the illustrative embodiment, the testing 5028, evaluation5030 and adjustment 5032 stages can be conducted with the systemoperating in normal flow mode. In normal flow mode, the operator cantest the function of the liver under normal or near normal physiologicblood flow conditions. Based on the evaluation 5030, the settings of thesystem can be adjusted in step 5032, if necessary, to modify the flow,heating and/or other characteristics to stabilize the liver inpreparation for transport to the recipient site in stage 5036. Thesystem with the preserved liver can be transported to the recipient siteat step 5036.

C. Preparation for Transplant

1. Final Flush/Cool Liver

In certain embodiments, before the liver is removed from the system 600and/or implanted into a recipient, the liver can be flushed by a finalflush solution to, for example, remove any residual blood and/or runtimeperfusion solution. The composition of the final flush solution isdescribed in detail above.

In certain embodiments, prior to the removal of the liver from the organcare system 600, the liver can be cooled again to a temperature at about4° C. to 10° C., 5° C. to 9° C., 5° C. to 8° C., 4° C., 5° C., 6° C., 7°C., 8° C., 9° C., or 10° C., or a temperature within any range boundedby the value described herein. The liver can be cooled by contact withice or refrigeration of the liver preservation chamber. In someembodiments, the system 600 can include a cooling unit that isconfigured to cool the liver directly and/or cool the fluid circulatingin the system 100. The final flush solution can also be chilled firstand then used to flush the liver to cool the liver. Thus, in theseembodiments, the liver can be finally flushed and cooled simultaneously.Once the liver is prepared and cooled down to a proper temperature, itcan be ready to be transplanted into a suitable recipient.

For example, in some embodiments, the liver is cooled and flushed whileon the system 600. The user can connect a one liter bag of chilled flushsolution to the flush port of the hepatic artery (e.g., port 4301) butleaves the port closed. The user connects two one liter bags of chilledflush solution to the flush port of the portal vein (e.g., port 4302)but leaves the port closed. The user connects a flush collection bag tothe perfusion module to the perfusate collection port located just afterthe perfusion module's pump compliance chamber (e.g., port 4309). Theuser can then apply a standard surgical clamp to the perfusion moduletubing just before the split to the hepatic artery and portal veinsimultaneous with the turning off of the circulatory pump 106. Thehepatic artery and portal vein flush ports can be opened so that theflush solution will enter the hepatic artery and the portal vein. Theperfusate collection bag can be unclamped so that the mixture ofperfusate and flush solution fills the bag rather than filling the organchamber.

In the event that a decision is made to cool the liver at the end ofpreservation, then the following exemplary procedure can be used:

1. Obtain and set-up a Heater Cooler unit (placed near OCS, electricalline plugged in, power ON, water circuit controls ON, water circuitvalve OFF). Do not connect Heater Cooler water lines to Liver PerfusionModule gas exchanger water lines yet.

2. Set Heater Cooler water circuit temperature to near the current livertemperature (e.g., approximately 37° C.) and allow it to reachtemperature.

3. Connect Hansen quick connect equipped Heater Cooler water lines toLiver Perfusion Module oxygenator water lines.

4. Turn the heater 100 OFF.

5. Set water circuit temperature of Heater Cooler to a lower temperaturethan the liver but not more than 10° C. lower and open the valve of thewater lines to allow flow to the Liver Perfusion Module gas exchanger114. As the actual temperature of the perfusion fluid, as reflected onthe user interface, approaches the Heater Cooler water temperature setpoint, adjust the Heater Cooler water temperature set point lower, butnot more than 10° C. lower than the perfusate/liver temperature, inincrements and keep repeating until the blood/liver have reached thedesired temperature.

6. When the liver temperature has reached the desired temperature,remove the liver from the system 600.

While the foregoing has focused on final flush and cooling of a liver, asimilar or identical procedure can be used when preserving other organs.For example, in some embodiments, the foregoing final flush/coolingtechnique can be applied to a heart and/or lung that is being preservedby the system 600.

VII. EVALUATION

In some embodiments of the disclosed subject matter, various techniquesor methods to assess the viability of the liver while the liver ispreserved on the organ care system 600 are provided (e.g., viability fortransplant). Generally, biomarkers known in the art for evaluating liverfunctions, e.g., liver enzymes, and known imaging techniques can be usedto evaluate the biological functions and status of the liver.Additionally, because the liver preserved on the organ care system 600is readily accessible to the operator, techniques not easily availableto the health care profession in vivo, e.g., visual observation of theliver or palpation of the liver, can also be used. Based on theevaluation results, one or more parameters of the organ care system 600,e.g., nutrients or oxygen content in the perfusion fluid or the flowrate and flow pressure of the perfusion fluid, can be adjusted toimprove the viability of the liver.

In some embodiments, the perfusion parameters of the organ care system600 can be used to evaluate the viability of the liver. Specifically, incertain embodiments, the perfusion liquid flow pressures in thecannulated hepatic artery and/or portal vein can be measured as anindicator of the liver viability. In some embodiments, a stable flowpressure in the range of 50-120 mmHg in the hepatic artery line canindicate that the preserved liver is receiving sufficient essentialnutrient supply. For example, in some embodiments, a stable flowpressure of about 50, 60, 70, 80, 90, 100, 110, 120 mmHg, or a pressurein any range bounded by the values noted here can indicate that thepreserved liver is receiving sufficient essential nutrient supply. Aflow pressure outside this range can indicate a leak or blockage in thesystem, or suggest to the operator to adjust the flow pressure to ensureproper nutrient supply to the liver. In other embodiments, the perfusionliquid flow rate in the cannulated hepatic artery and/or portal vein canbe measured as an indicator of the liver viability. In otherembodiments, a flow rate in the range of 0.25-1 L/min for the hepaticartery can indicate that the preserved liver is receiving sufficientessential nutrient supply. For example, in some embodiments, a flow rateof about 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70,0.75, 0.80, 0.85, 0.90, 0.95, 1.00 L/min or a rate in any range boundedby the values noted here for the hepatic artery can indicate that thepreserved liver is receiving sufficient essential nutrient supply. Aflow rate outside this range can indicate a leak or blockage in thesystem, or suggest to the operator to adjust the flow rate to ensureproper nutrient supply to the liver. The flow rate and pressure can bemeasured using the pressure and/or flow sensors described herein.

In some embodiments, visual observation or examination of the liver canbe used to assess the liver viability. For instance, a pink or red colorof the liver can indicate that the liver is functioning normally, whilea dark or blueish color of the liver can indicate that the liver isfunctioning abnormally or deteriorating (e.g., is being hypoperfused).In other embodiments, palpation of the liver is used to assess itsviability. When the liver feels soft and elastic, the liver is likelyfunctioning normally. On the other hand, if liver feels tense or stiff,the liver is likely functioning abnormally or deteriorating (e.g., isbeing hypoperfused).

A. Bile Production

In some embodiments, because the bile duct is cannulated and connectedto a reservoir of the organ care system 600, the color and amount ofbile produced by the liver can be easily examined to evaluate the liverviability. In certain embodiments, black or dark green color bile canindicate normal liver function while a light or clear color of the bilecan indicate that the liver is not functioning properly ordeteriorating. In still other embodiments, the amount of the bileproduction can be used to evaluate the liver viability as well (and/orthe determination that the liver is producing bile at all can be a goodindicator). While any bile production can be a sign of a healthy liver,generally, the more the bile produced, the better the liver function. Incertain embodiments, a bile production of from about 250 mL to 1 L, 500mL to 1 L, 500 mL to 750 mL, 500 mL, 750, or 1 L per day or in anyranges bounded by the values noted herein suggests that the liverpreserved on the organ care system 600 is functioning normally andviable.

B. Blood Gas, Liver Enzymes, and Lactate Measurements/Trends

In some embodiments, various biomarkers or compounds in the perfusionliquid can be used to evaluate the liver viability. For instance,metabolic assessment of the liver can be conducted by calculating oxygendelivery, oxygen consumption, and oxygen demand. Specifically, theamount of oxygen and carbon dioxide dissolved in the perfusion liquidcan be monitored as indicators of the liver function. The concentrationsof these gases in the perfusion liquid (or the blood product) before andafter liver perfusion can be measured and compared. In certain specificembodiments, the concentrations of the oxygen and carbon dioxide can bemeasured by various sensors within the organ care system 600's flowmodule or subsystem.

In some embodiments, the perfusion fluid before and after liverperfusion (e.g., the perfusion fluid entering the hepatic artery andexiting the IVC) can be sampled using respective oxygen concentration(or other) sensors and the relevant concentrations of the oxygen andcarbon dioxide can be measured. A significant increase of the carbondioxide concentration in the perfusion liquid after liver perfusion,and/or a significant decrease of the oxygen concentration after theliver perfusion, can indicate that the liver is performing its oxidativemetabolic functions well. On the other hand, a minor or no increase ofthe carbon dioxide concentration in the perfusion liquid after liverperfusion, and/or minor or no decrease of the oxygen concentration afterthe liver perfusion, can indicate that the liver is not performing itsoxidative metabolic functions properly. The difference of PVO₂ and PaO₂can indicate metabolically active, aerobically active metabolism, oxygenconsumption.

In some embodiments, liver function blood test (LEFTs) can be conductedto assess the liver viability. Specifically, in some embodiments,aspartate aminotransferase (AST), alanine aminotransferase (ALT),alkaline phosphates, albumin, bilirubin (direct and indirect) can bemeasured to evaluate the liver functions. In other embodiments, thefibrinogen blood level can be measured as well as an indication of theliver cells' ability to produce clotting factors.

AST, ALT are liver enzymes and are well-accepted clinical liverbiomarkers used for assessing the liver functions and/or suitability fortransplant. However, the measurements of AST and ALT are usuallycomplicated and time-consuming, and are typically conducted in hospitalor lab settings. Thus, there exists a need for a sensitive and simpleindicator for determining the status of the preserved liver. Lactate,also called lactic acid, is a byproduct/end product of anaerobicmetabolism in living cells/tissues/organs. Lactate is generated whenthere is no or low oxygen in the cell to metabolize glucose for basicenergy production through the glycolysis pathway. Applicant hasdiscovered that the level of the lactate in the perfusion liquid, e.g.,the perfusion liquid exiting from the IVC, can be measured as asurrogate for measuring the AST levels. The lactate concentration can bemeasured quickly and simply, which provides significant advantages overthe time-consuming liver enzyme measurement. Based on the quick feedbackprovided by lactate measurements, one or more parameters of the organcare system 600, e.g., flow rate, pressure, and nutrient concentrations,can be adjusted to preserve or improve the liver viability quickly.Stated differently, lactate values (e.g., arterial lactate trends) canbe correlated to and be indicative of AST levels. For example, a series(over time) of lactate measurements trending lower can correlate and/orbe indicative of a trending lower AST. In some embodiments, lactatemeasurements can be taken in the measurement drain 2804, although thisis not required and can occur at any other location in the system 100.Additionally, in some embodiments, the system 600 can be configured toobtain lactate measurements over time from a single location, adifferential between a lactate value entering and exiting the liver, andover time at multiple locations.

C. Imaging

In still other embodiments, various other methods known in the art canbe used to assess the liver viability. In some specific embodiments,ultrasound analysis of the liver can be conducted to assess liverparenchyma, intra- and extra-hepatic biliary tree. Other non-limitingexamples of imaging techniques include Magnetic Resonance Imaging (MRI),Computed Tomography (CT), Positron Emission Tomography (PET),fluoroscopy, Transjugular Intrahepatic Portosystemic Shunt (TIPS), allof which can be used to assess the liver and detect abnormalities. Forexample, when examining an ultrasound of the liver, the doctor canexamine sinusoidal dimensions, potential obstructions in the bile duct,and/or generalized blood flow.

D. Pathology/Biopsy

In still other embodiments, liver biopsy can be used to assess the liverviability. In liver biopsy, a small piece of liver tissue is removed soit can be examined under a microscope for signs of damage or disease.Because the liver is preserved ex vivo on the organ care system 600, itis readily accessible and the biopsy can be easily conducted.

VIII. THE CLOUD

During operation, the system 600 generates information about the systemitself and/or the organ being maintained. In some embodiments of thesystem 600, this information can be stored in an internal memory such asRAM or ROM. In some embodiments the information generated by the system600 can also be transmitted to a remote storage location such as in theCloud. The Cloud can be, for example, a series of remote interconnectedcomputers that are configured to provide data and/or services over theInternet. The Cloud can store the information, perform analysis on theinformation, and/or provide the information to one or more third partiesand/or stakeholders.

In some embodiments of the system 600, the system can include amultimodal communication link between itself and one of more otherlocations, such as servers in the Cloud. This communication link can becontrolled by the controller 150 (e.g., via the data managementsubsystem 151), although this is not required and other components canbe used to control communication. The controller 150 can be configuredto provide real-time information about the system 600 and/or the organcontained therein to one or more remote locations while the system is atthe donor hospital, is in transit, and/or is at the recipient hospital.In some embodiments, communication can be accomplished usingcommunication link such as a wired network connection (e.g., Ethernet),a wireless network connection (e.g., IEEE 802.11), a cellular connection(e.g., LTE), a Bluetooth connection (e.g., IEEE 802.15), infraredconnection, and/or a satellite-based network connection. In someembodiments, the controller 150 can maintain a priority list ofconnections favoring those connections which are more reliable such as ahardwired Internet connection and/or Wi-Fi over less reliable cellularand/or satellite connections. In other embodiments, the priority listcan be generated with a preference for lower-cost transmission mediumssuch as Wi-Fi.

The system 600 can be configured to communicate with the Cloud, andultimately remote parties via one or more techniques. For example, thesystem 600 can be configured to communicate with a server in the Cloudand/or directly with one or more remote computers. In some embodiments,the system 600 can be configured to: i) send communications such asemails and/or text messages to predetermined addresses, ii) upload datafiles to remote storage locations using, for example, FTP, iii)communicate with a dedicated remote server to provide information in aproprietary format, and iv) receive information downloaded from theCloud and/or other remote computers. In some embodiments, the controller150 can transmit/receive the information on a regular schedule, whichcan vary depending on which phase of operation the system is in. Forexample, the controller 150 can be configured to provide updates everyfive minutes while the system 600 is located at the donor hospital,every 15 seconds while in transport, and/or every 15 seconds while thesystem 600 is located at the receiving hospital. The controller 150 canalso be configured to transmit/receive information in a secure manner,such as using encryption and/or with a timestamp.

The controller 150 can be configured to provide various types ofinformation to the Cloud and/or remote location such as: an offer for anorgan, system readiness information, battery charge level, gas tanklevel, status of the solution infusion pump, flow rates, pressure rates,oxygenation rates, hematocrit levels, lactate levels, temperaturelevels, the flow rate at which the pump 106 is set, the temperature atwhich the heater 110 is set, the position of the flow clamp 190, some orall of the information displayed on the user interface (e.g.,circulatory and infusion flow rates, pressures, oxygenation levels,hematocrit levels), geographic location, altitude, a copy of thedisplayed interface itself, waveforms displayed on the user interface,alarm limits, active alarms, screen captures of the user interface,photographs (e.g. captured using an onboard camera), HAP/HAF/Lacatetrends, historical usage information about the system 600 (e.g., thenumber of hours it has been used), and/or donor information. Inheart/lung embodiments additional information such as AOP and/or PEEPcan be provided. Essentially, any piece of information that iscollected, generated, and/or stored by the system 600 can be transmittedto the Cloud and/or a remote computer.

The controller 150 can be configured to receive various types ofinformation from the Cloud and/or a remote location such as:instructions from a remote user, a “pull” demand for data from a remotelocation, control inputs, information about the organ recipient, and/orsystem updates.

In some embodiments, using the information provided by the system 600, auser that is remote from the system 600 can effectively remotely viewthe same user interface that is displayed on the system 600.Additionally, in some embodiments, a user that is remote to the system600 can also remotely control the system 600 as if they were there inperson. In some embodiments, the remote view can be an enhanced versionof what is seen by the attending user. For example, the user interfacecan be presented in a similar format so that the remote user canvisualize what the attending user sees, but the remote view can beenhanced so that it also displays additional information to providecontext for the remote viewer. For example donor demographics,geographic location, trends, and/or assessment results can also bedisplayed. A remote user can also be provided with virtual buttonsand/or controls, matching those found on the system 600, which can beused to remotely control operation of the system 600.

In some embodiments, one or more technicians can remotely connect to andaccess the system 600 to perform diagnostics, update the system, and/orremotely troubleshoot issues. In some embodiments, remote technicalassistance can be limited to times when the system 600 is not being usedto preserve an organ.

In some embodiments, the information provided by the system 600 can bepresented to a remote user through a web portal, mobile application,and/or other interface.

In some embodiments, access to the information provided by the system600 can be limited to one or more registered users such as, surgicalstaff at the recipient hospital, a technical support team, and/oradministrators. In some embodiments, access to information provided bythe system 600 can be tied to an electronic medical file of therecipient. For example, the Cloud-based server can access one or moreelectronic medical files of the recipient to determine, for example:parties expressly identified as being able to have access to therecipient's health data, parties associated with organizations that areidentified as being able to have access to the recipient's health data,and/or individuals working at medical facilities that are within acertain geographic distance of the recipient.

As described herein, sometimes during transport samples of perfusionfluid can be withdrawn for external analysis. In these instances,however, the data obtained through the external analysis isdisassociated with the information contained within the system 600.Thus, in some embodiments, the user interface provided by the system 600can be configured to allow a user to input and store externallygenerated data about the organ. For example, if the attending userwithdraws a sample of the perfusion fluid in order to perform a lactatemeasurement in an external analyzer, the attending user can then inputand store the result in the system 600 along with the data that isgenerated by the system 600 itself. Along with the result itself, theuser can also provide timestamp information and a description of theinformation. The information inputted by the user can be stored,processed, downloaded, and/or transmitted by the system 600 as if itwere generated internally. In this manner, the system 600 can keep acomplete record of all information relating to the organ while it was exvivo regardless of whether the information was generated internally inor externally from the system 600.

In operation, referring to FIG. 26, a process 6600 describes anexemplary embodiment of how the system 600 can be used with aCloud-based communication/storage system. The process 6600 is exemplaryonly and not limiting. For example, the stages described therein can bealtered, changed, rearranged, and/or omitted. The process 6600 assumesthat the system 600 is in communication with a remote cloud-based serverand that the system is being used to transport an organ, although thisis not required. This process can be adapted to be used, for example,while an organ is being treated ex vivo for implantation back into theoriginal patient rather than being transplanted into a new recipient.

At stage 6605, an offer for an organ can be presented to the retrievalhospital by the organization that controls organ allocation (e.g., anorgan procurement organization). Through a web portal to the system 600,the retrieval hospital's staff can query the readiness (e.g. batterycharge level, gas level) of the system 600 and can enter informationabout the donor. The information can be transferred to the system 600via the server.

At stage 6610, clinical support that have registered with the server ason-call staff can be alerted to the upcoming transport session via anemail, a text message, an automated phone call, and/or any othercommunication means. The clinical support staff can be, for example,staff employed by the manufacturer of the system 600.

At stage 6615, which typically occurs during transport, the system 600can transmit system/organ status information to a Cloud-based server viaa communication link. The information transmitted to the server can bereviewed in an online portal by third parties such as the transplantsurgeon, support staff, and/or any other permitted party (all of whichcan be at different geographic locations). In some embodiments, theserver can perform additional processing on the information receivedfrom the system 600 to generate new information, which can then bepresented back to the system 600 and/or to third parties. Theinformation displayed to the user on the system 600 can be transmitted(e.g., either the underlying data and/or the image itself) to theserver, for example, unsolicited once every 2 minutes. The data can thenbe stored with a timestamp on the server. For example, in someembodiments, each time information is received by the server from thesystem 600, this can be placed in a row of an Excel spreadsheet.Additionally, during the stage 6615, remote users that are viewing theinformation through the portal can “pull” (demand) a screenrefresh/snapshot of the data from the OCS rather than waiting for thenext 2-minute sample to be “pushed.” Additionally, in some embodiments,the remote parties can remotely control the operation of the system 600via a remote interface.

The remote view can be an enhanced version of what is displayed on themonitor of the system 600. It can be presented in a similar format sothat the remote user can visualize what the attending user sees. In someembodiments, however, the remote view can also be enhanced so that italso displays additional information to provide context for the remoteviewer, such as donor demographics, trends, and assessment results.

The system 600 can assert alerts through the server to remote thirdparties such as the transplant surgeon and/or clinical support team. Theattending user can trigger contact from one of more remote third partiesvia a monitor menu action. For example, the attending user can send arequest for assistance to technical support who can receive an alertvia, for example, text message and/or email and call or otherwisecontact the attending user.

The system 600 can automatically assert alerts in certain criticalconditions (e.g. HAP>120, or PVP>20 mmHg). The attending user can alsosnap a photograph using a camera that is integrated into the system 600(e.g., integrated into the operator interface module 146). The image canautomatically be pushed to the server by the system 600.

During stage 6615, the system 600 can automatically provide informationto the server and/or other remote computer at regular intervals such asevery 15 seconds, every two minutes, every five minutes, or every 10minutes. In some embodiments, information transmitted between the system600, the server, and/or the third party can occur in real time so thatthe remote party can have real time access to and/or control over thesystem 600 as if they were there in person. In some embodiments, theattending user and/or any other remote parties can initiate anunscheduled information transfer. In some embodiments, if thecommunication link of the system 600 has been disabled or is inoperable(e.g., during air transport), the controller 150 can be configured tocontinue generating regular status updates and store them fortransmission once the communication link has been re-enabled.

At stage 6620, which typically occurs at the end of the transportsession, session files from the system 600 can be pushed to the server.The information provided to the server can include, for example, thetrend, error, blood sample, and event files. Preference can be given toWiFi before cellular link for data transmission, to minimize cost.

IX. POSSIBLE BENEFITS

Some embodiments of the system 600 described herein can provide one ormore benefits. For example:

Depending on the type of procedure being performed, manually controllingan organ preservation system can be a labor-intensive process that canrequire specialized training. Additionally, as with any medicalprocedure, manual control can also be prone to mistakes by thosecontrolling the system. Thus, in some embodiments, the system 600 canautomatically control itself in real time. For example, the controller150 can be configured to automatically control the flow rate of the pump106, the operation of the gas exchanger 114, the temperature of theheater 110, the operation of the flow clamp 190 (when an automated clampis used), and/or the transmission of information to the Cloud. Thecontroller 150 can be configured to control operation of the system 600based upon feedback information from, for example, the sensors containedtherein.

Providing automated control of the system 600 can result in improvedusability, can reduce the possibility of error, and can reduce the laborintensity of transporting an organ. For example, automating the controlprocess can compensate for user variability that can exist whendifferent people control the system. For example, even if two usersreceive the same training, one user's judgment may differ from anotherwhich can result in inconsistent levels of care across the two users. Byautomating the control process, a level of consistency between operatorscan be achieved in a manner that is otherwise difficult to do.Additionally, providing automated control can also provide better carefor the organ while ex vivo by updating operational parameters of thesystem 600 more quickly than is possible with manual control.

The techniques described herein can also improve the utilization ofdonor organs that are currently not being utilized due to limitations ofcold storage methods. In existing cold storage methods, many organs goto waste because the organ cannot be transported to a recipient beforeit suffers damage as a result of cold storage. This results in manyorgans that are otherwise suitable for transplantation going to wasteeach year. Using the techniques described herein, the amount of timethat an organ can be maintained in a healthy ex vivo state can begreatly extended thereby increasing the potential donor and recipientpool.

The techniques described herein can also help improve the assessment ofwhether an organ is suitable for transplant into a recipient. Forexample, using a liver example, visual observation or examination of theliver can be used to assess the liver viability. For instance, a pink orred color of the liver can indicate that the liver is functioningnormally, while a gray or dark color of the liver can indicate that theliver is functioning abnormally or deteriorating. In other embodiments,palpation of the liver can be used to assess its viability. When theliver feels soft and elastic, the liver is likely functioning normally.On the other hand, if liver feels tense or stiff, the liver is likelyfunctioning abnormally or deteriorating.

In still other embodiments, because the bile duct is cannulated andconnected to a reservoir of the system 600, the color and amount of bileproduced by the liver can be easily examined to evaluate the liverviability. In certain embodiments, black or dark green color bileindicates normal liver function while a light or clear color of the bileindicates that the liver is not functioning properly or deteriorating.In still other embodiments, the amount of the bile production can beused to evaluate the liver viability as well. Generally, the more thebile produced, the better the liver function. In certain embodiments, abile production of from about 250 mL to 1 L, 500 mL to 1 L, 500 mL to750 mL, 500 mL, 750, or 1 L per day or in any ranges bounded by thevalues noted herein suggests that the liver preserved on the organ caresystem 600 is functioning normally and viable. Many of the foregoingtechniques can be difficult, if not impossible when the organ is invivo.

X. EXAMPLES

Experimental tests and results relating to the some embodiments aredescribed below. As described below, experimental tests includedmultiple studies and phases. Phase I included studies of 27 liversamples including two groups of organs on the above OCS system for up to12 hours. Phase II included replicating the clinical steps of liverretrieval, preservation and simulated transplantation processes formultiple sample livers for 4 hours of simulated transplant. Phase IIIincluded replicating clinical steps of liver retrieval, preservation andsimulated transplantation processes for multiple sample livers for 24hours of simulated transplant.

A. Phase I

Groups A and B of organs were used for Phase I. Objectives for Phase Iinclude: (1) To optimally perfuse and preserve Livers on the OCS systemfor up to 12 hours using oncotic adjusted red blood cells (“RBCs”) basednutrient enriched perfusate; (2) maintain stable near—physiologicalheamodynamics (pressure and flow) for both the portal and the hepaticarterial circulation; (3) enable monitoring of organ functionality andstability on the OCS by monitoring bile production rate, liver enzymestrends, stable PH and arterial lactate levels; and (4) histopathologyassess the organ post OCS.

The animal model used for the test was the swine model, including 70-95kg Yorkshires swine. The Yorkshires swine was used as a model due to itssimilarity to human anatomy and size relative to human adult organ size.The perfusate for the test was red blood cell based. Given that theliver is a highly metabolic active organ, a perfusate with an oxygencarrying capacity and nutrient enriched would be ideal for the organ,mimicking it's in-vivo environment and satisfying the organ's highmetabolic demand.

Liver is unique by its dual blood supply. As described previously, theliver gets its blood supply through the portal vein (PV) and the hepaticartery (HA). Portal circulation is a low-pressure circulation (5-10 mmHg) and the hepatic arterial circulation delivers high-pressurepulsatile blood flow (70-120 mm Hg). Stable perfusion parameters andhemodynamics indicate stable perfusion. Lactate levels were used as amarker of adequate perfusion because lactate is one of the mostsensitive physiologic parameters, and is thus a good indicator of theadequacy of perfusion. Lactate is produced under anaerobic conditionsdenoting inadequate perfusion, and the trend of lactate level is asensitive marker for perfusion adequacy assessment. AspartateAminotransferase (“AST”) is a standard marker used clinically to assesslivers, and was also used as a marker of viability. The trend of ASTlevel is another marker and indicator of the organ viability. Bileproduction is a unique function of the liver. Bile production monitoringis another marker for the organ viability and functionality.

Phase I included studies of 27 liver samples. Of those, Group A included21 samples that were preserved on the OCS for 8 hours using cellularbased perfusate. Group B included 6 samples that were preserved on theOCS for 12 hours using cellular based perfusate.

The following protocol was applied for phase I groups A and B testing.

First, animal prep, organ retrieval, cannulation and Pre-OCS flush isdescribed. Each 70-95 kg Yorkshires Swine was sedated in its cage byinjecting a combination of Telazol and Xylazine intramuscularlyaccording to the following dose: 6.6 mg/kg Telazol and 2.2 mg/kgXylazine. The animal was then intubated, an IV line established, thenthe animal was transferred to the OR table in supine position, thenconnected to the ventilator and anesthesia machine. The liver wasexposed through a right subcostal incision, and the heart through mediansternotomy incision. The hepatic artery (HA), portal vein (PV) and thecommon bile duct were isolated. The right atrium and the superior venacave were then isolated and cannulated for blood collection. Then 2-3liters of blood were collected from the animal using a 40 Fr venouscannula through the right atrium. The collected blood was then processedthrough a cell saver machine (Haemonetics Cell Saver 5+) to collectwashed RBCs. Topical cooling was applied to the liver during the bloodcollection time. Then the liver was harvested.

After harvesting the liver, the hepatic artery (HA), portal vein (PV),the common bile duct, supra hepatic cava and infra hepatic cave wereisolated and cannulated using the appropriate size for each. Exemplarysized cannulas include 14 Fr, 16 Fr, 18 Fr for the hepatic arterycannula, 40 Fr and 44 Fr for the portal vein cannula, 12 Fr and 14 Frfor the common bile duct cannula, 40 Fr for the supra-hepatic vena cava,and 40 Fr for the infra-hepatic cava.

The liver was then flushed using 3 L of cold PlasmaLyte® solution, eachliter was supplemented with Sodium bicarbonate (NHCO3) at 10 mml/L,Epoprostenol Sodium at 2 mics/L, Methylprednisolone at 160 mg/L. Oneliter was delivered through the hepatic artery pressurized at ˜50-70mmHg. Two liters were delivered through the portal vein by gravity.

After cannulation, the organ was preserved on the OCS at 34° C. for 12hours using oncotic adjusted RBCs based perfusate. The OCS-liver systemprime perfusate included washed red blood cells, albumen 25%,PlasmaLyte® solution, dexamethasone, sodium bicarbonate (NaHCO₃) 8.4%,adult multivitamins for infusion (INFUVITE®), calcium gluconate 10% at(100 mg/ml), gram-positive antibiotic such as cefazolin, and a gramnegative antibiotic such as ciprofloxacin. Table 7 below summarizes theliver prime perfusate composition and dose.

TABLE 7 OCS liver prime perfusate composition and dose OCS LiverPerfusate Composition Recommended Dose Washed Red Blood Cells (pRBCs)1-2 L Albumin 25% 400 mls PlasmaLyte ® Solution 700-800 mlsMethylprednisolone 500 mgs Dexamethasone 20 mgs Sodium Bicarbonate(NaHCO3) 8.4% 50-70 mmol Adult Multivitamins for infusion INFUVITE ® 1unit Calcium Gluconate 10% (100 mg/ml) 10 mls Antimicrobials:Gram-positive antibiotic: Cefazolin 1 gm Gran-negative antibiotic:Ciprofloxacin 100 mg

In addition to OCS-Liver circulating perfusate mentioned above, thefollowing were delivered to the perfusate as continuous infusion usingan integrated Alaris infusion pump: Total Parenteral Nutrition (TPN):CLINIMIX E (4.25% Amino Acid/10% Dextrose); PLUS Insulin (30IU), Glucose(25 g) and 40,000 units of Heparin; Prostacyclin infusion as needed:(epoprostenol sodium) to optimize the Hepatic Artery Pressure; BileSalts (Taurocholic acid sodium): as needed for Bile Salt Supplement.Table 8 below illustrates the liver perfusate infusions and rate.

TABLE 8 OCS liver perfusate infusions and rate Dose Continuous InfusionMix Total parenteral nutrition (TPN) Mix: 30-50 ml/hr CLINIMIX E TPN(4.25% Amino Acid/10% Dextrose); PLUS Insulin 30 IU Glucose 25 gmsHeparin 40,000 units As Needed Additives Prostacyclin infusion as neededto control Hepatic 0-6 mics/hr artery pressure - e.g. EpoprostenolSodium 0.5 mg Bile Salts 0-10 ml/hr Taurocholic acid sodium (1 gm/50 ml)NaHCO3 8.4% to correct metabolic acidosis 1.5 meq/1 bas excess

The Liver was perfused on the OCS by delivering blood based, warm,oxygenated and nutrient enriched perfusate through the hepatic arteryand the portal vein. Once the liver was instrumented on the OCS and allcannulae were connected, pump flow was increased gradually and veryslowly to achieve the target flow over 10-20 minutes. While the liverwas warming up to the temperature set point, the flow control clamp wasadjusted to maintain a 1:1 to 1:2 flow ratio between the HA and PV. Thevasodilator agent flow rate was adjusted as needed to manage the hepaticartery pressure. An arterial blood sample was collected within the first15-20 minutes.

The following perfusion parameters were maintained during perfusion onthe OCS-liver device: Hepatic Artery Pressure (mean HAP): 75-100 mmHg;Hepatic Artery Flow (HAF): 300-700 ml/min; Portal Vein Pressure (meanPVP): 4-8 mmHg; Portal Vein Flow (PVF): 500-900 ml/min; PerfusateTemperature (Temp): 34 C; Oxygen gas flow 400-700 ml/min.

Lactate levels on the OCS-Liver Perfusion were collected according tothe following sampling scheme. One OCS liver arterial sample wascollected within 10-20 minutes from a start of perfusion on theOCS-Liver device. Samples continued to be collected from the device atapproximately hourly intervals until lactate level was trending down, atwhich point the lactate samples were taken every 2 hours or after anyactive HAF or HAP adjustments. Baseline Liver Enzyme was measured fromthe animal. Liver Enzyme was collected and assessed on the OCS every twohours starting at the second hour.

Post OCS Histopathology Sampling.

At the end of the preservation time, OCS perfusion was terminated. Theliver was disconnected from the device and all cannulas were removed.Specimens were collected from the Liver and saved in 10% formalin forHistopathology assessment. A section of the Liver was collected for thewet/dry ratio. The section weight was recorded before and after 48 hoursin an 80° C. hot oven. The wet/dry ration was then calculated accordingto the following formula: Water Content (W/D ratio)=1−(EndingWeight/Starting Weight).

A liver was considered acceptable if it met acceptance criteria,including: stable perfusion parameters throughout preservation on theOCS for HAF, HAP, PVF and PVP; stable or trending down arterial lactate;continuous bile production with a rate of >10 ml/hr.; stable or trendingdown liver enzymes (AST); and normal and stable perfusate PH.

The Phase I, Group A, 21 samples successfully met the above identifiedacceptance criteria. The data for hepatic artery flow over 8 hours ofOCS liver perfusion shown in the graph in FIG. 31 demonstrates that OCSperfused swine livers demonstrated stable perfusion, as evidenced by theHepatic Artery Flow (HAF) trend throughout the course of 8 hourspreservation on OCS. The data for portal vein flow over 8 hours of OCSliver perfusion shown in the graph in FIG. 32, which shows PVF trendthroughout the course of the 8 hour preservation on OCS, demonstratedstable perfusion, as evidenced by the stable Portal Vein Flow (PVF)trend throughout the course of 8 hours preservation on OCS. FIG. 33shows a graphical depiction of hepatic artery pressure versus portalvein pressure throughout the 8 hour OCS-liver perfusion. FIG. 33illustrates that OCS perfused swine livers demonstrated stable perfusionpressure, as evidenced by the stable portal vein pressure and thehepatic artery pressure throughout the course of the 8 hourpreservation.

FIG. 34 is a graphical depiction of arterial lactate levels over the 8hour OCS liver perfusion. FIG. 34 shows that OCS perfused swine liversdemonstrated excellent metabolic function, as evidenced by their abilityto clear lactate and trending down lactate throughout the course of 8hours preservation on OCS. FIG. 35 is a graphical depiction of totalbile production over the 8 hour OCS liver perfusion. FIG. 35 shows thatOCS perfused livers continued to produce bile at a rate of >10 ml/hr.throughout the course of the 8 hour preservation on OCS indicatingpreserved organ functionality. FIG. 36 is a graphical depiction of ASTlevel over the 8 hour OCS liver perfusion. Aspartate Aminotransferase(AST) is a standard marker clinically used to assess livers. FIG. 36graph demonstrates that OCS perfused livers exhibited a trending downAST levels over the course of 8 hours perfusion on the OCS, indicatinggood liver functionality. FIG. 37 is a graphical depiction of ACT levelover the 8 hour OCS liver perfusion. As shown in FIG. 37, activatedclotting time (ACT) was maintained above 300 seconds over the course of8 hours of perfusion on the OCS. FIG. 38 is a graphical depiction ofoncotic pressure throughout the course of 8 hours preservation on OCS.As shown in FIG. 38, oncotic pressure remained stable on the OCS.

FIG. 39 is a graphical depiction of bicarb levels over the 8 hour OCSliver perfusion. As shown in FIG. 39, Bicarb (HCO3) levels weremaintained within normal physiologic ranges over the course of 8 hoursperfusion on the OCS with very minimal doses required of HCO3 forcorrection, indicating a stable liver metabolic profile. FIG. 40 is adepiction of the detected pH levels throughout the course of 8 hourspreservation on OCS. As shown in FIG. 40, stable and normal pH wasmaintained over the course of 8 hours perfusion on the OCS with no orminimal need to add HCO3 for correction, indicating a good functioningand adequately perfused organ.

FIG. 41 shows images of tissues taken from samples in Phase I, Group A.Histological examination of parenchymal tissue and bile duct tissueshows normal liver sinusoidal structure with no evidence of necrosis orischemia and normal bile duct epithelial cells indicating adequateperfusion and lack of ischemic injury.

The results observed for Phase I Group B, organs maintained for 12hours, exhibited similar acceptable results to those in Group A.

As in Group A above, in Phase I Group B a liver was consideredacceptable if it met acceptance criteria, including: stable perfusionparameters throughout preservation on the OCS for HAF, HAP, PVF and PVP;stable or trending down arterial lactate; continuous bile productionwith a rate of >10 ml/hr.; stable or trending down liver enzymes (AST);and normal and stable perfusate PH.

FIG. 42 depicts Hepatic Artery Flow of a 12 hr OCS Liver Perfusion. Asillustrated, the graph of FIG. 42 shows that OCS perfused swine liversdemonstrated stable perfusion, as evidenced by the Hepatic Artery Flow(HAF) trend throughout the course of 8 hours preservation on OCS.

FIG. 43 depicts Portal Vein Flow of a 12 hr OCS Liver Perfusion. Asillustrated, the graph of FIG. 43 illustrates OCS perfused swine liversdemonstrated stable perfusion, as evidenced by the stable Portal VeinFlow (PVF) trend throughout the course of 12 hours preservation on OCS.

FIG. 44 depicts Hepatic Artery Pressure vs. Portal Vein Pressure in a 12hr OCS-Liver Perfusion. The graph of FIG. 44 demonstrates that OCSperfused swine livers demonstrated stable perfusion pressure, asevidenced by the stable Portal Vein Flow (PVP) and the Hepatic ArteryPressure (HAP) trend throughout the course of 12 hours preservation onOCS.

FIG. 45 depicts Arterial Lactate in a 12 hr OCS-Liver Perfusion. Thegraph of FIG. 45 shows that OCS perfused swine livers demonstratedexcellent metabolic function, as evidenced by their ability to clearlactate and trending down lactate levels throughout the course of 12hours preservation on OCS.

FIG. 46 depicts Bile Production in a 12 hr OCS-Liver Perfusion. Thegraph of FIG. 46 demonstrates that the OCS perfused Livers continued toproduce bile at a rate of >10 ml/hr throughout the course of 12 hourspreservation on OCS indicating well preserved organ function.

FIG. 47 depicts AST Level of a 12 hr OCS-Liver Perfusion. AspartateAminotransferase (AST) is a standard marker clinically used to assesslivers. The graph of FIG. 47 demonstrates that OCS perfused liversexhibited a trending down AST levels over the course of 12 hoursperfusion on the OCS. This indicates good liver functions.

FIG. 48 depicts ACT Levels in a 12 hr OCS-Liver Perfusion. Activatedclotting time (ACT) was maintained above 300 sec over the course of 12hours perfusion on the OCS, as illustrated in FIG. 48.

B. Phase II

Phase II, or Group C, included studies of 12 liver samples. Of those, 6samples were preserved on the OCS for 8 hours using cellular basedperfusate, and were then subjected to simulated transplant on the OCSfor 4 hours of preservation using whole blood as perfusate. The other 6samples were preserved for 8 hours using cold static preservation in UWsolution, and were then subjected to simulated transplant on the OCS for4 hours of preservation using whole blood as perfusate.

Objectives for Phase II include preserving the liver with OCS using warmperfusion for 8 hours using an RBCs based perfusate, followed by 45minutes of cold ischemia, then another 4 hours of OCS-Liver warmperfusion using whole blood, (a) to optimally perfuse and preserveLivers on the OCS system for 8 hours using oncotic adjusted RBCs-basednutrient enriched perfusate, (b) maintain stable near-physiologicalheamodynamics (pressure and flow) for both the portal and the hepaticarterial circulation, (c) enable monitoring of organ functionality andstability on the OCS by monitoring bile production rate, liver enzymestrends, stable PH and arterial lactate levels, (d) subject the organ to45 minutes of cold ischemia post the first 8 hours on the OCS, (e)followed by 4 hours of simulated transplant on the OCS using wholeblood, while monitoring and assessing the organ heamodynamic andperfusion parameters and monitoring organ functionality.

Simulated transplant on the OCS was used to minimize the confoundingvariables associated with orthotopic transplantation and to isolate thevariables to only the ischemia/reperfusion effects.

This group (C) of pre-clinical simulated transplant testing was expandedto include a control arm of cold stored swine livers using standard ofcare cold liver preservation solution. Except for the cold preservationphase, the protocol for this arm of the group was identical to the OCSsimulated transplant arm of the same group (C). The detailed protocoland results are described below.

Like Phase I, 70-95 kg Yorkshires swine were used as a test subject forPhase II. For this phase, two animals were used for each study, with thefirst animal as the organ donor, and a second animal as a blood donorfor the simulated phase of perfusion on the OCS.

In this simulated animal transplant model, the donor organ was exposedto the identical conditions of organ retrieval, preservation, andterminal cooling for transplantation as in orthotopic transplant. Theonly difference was that in the transplant phase the organ wasreperfused with another animal's un-modified whole blood in an ex-vivoOCS perfusion system to control for all the confounding variables oforthotopic transplants that may shadow the true impact of preservationinjury on the donor organ. The donor organ's function and markers ofinjury monitored during simulated transplant phase were identical to theones that would be monitored during orthotopic transplantation. Theacceptance criteria for Phase II samples were the same as those outlinedabove, and were measured during the 4 hours of simulated transplant.

Phase II, Simulated Transplant OCS arm, 6 samples (N=6).

This set was achieved by replicating all key clinical steps of liverretrieval, preservation and simulated transplantation processes in thefollowing sequence:

Donor Organ Retrieval (30-45 minutes): During this phase, the donororgan was retrieved, and cold flushed for 30-45 minutes to replicate theclinical condition of donor liver retrieval and instrumentation on theOCS Liver system. The same prep, organ retrieval, cannulation andpre-OCS flush were performed as described in Phase I.

Donor Liver Preservation on OCS (8 hours): During this phase, the donororgan underwent ex-vivo perfusion and assessment using OCS Liver system.During this phase, the liver was monitored and assessed hourly formarker of liver injury (AST level), marker for metabolic function(Lactate level), and bile production rate as a marker for liverfunction/viability. The same organ preservation was performed for thisgroup as the 8 hour preservation samples described in Phase I.

Post-OCS Preservation Cold Ischemia (45 minutes): During this phase thedonor liver was flushed using cold flush solution as specified in theproposed clinical protocol to replicate final cooling of the donor liverrequired for re-implantation. Donor livers were maintained cold for 45minutes to replicate the time required for performing there-implantation procedure in the recipient. Using the Final Flush lineincluded in the OCS Liver perfusion termination set, the liver wasflushed and cooled on the OCS using 3 L of Cold PlasmaLyte solutionsupplemented with Sodium bicarbonate (NHCO3) 10 mml/L, EpoprostenolSodium 2 mcg/L and Methylprednisolone 160 mg/L flush, supplying 1 literat ˜50-70 mmHg to the hepatic artery, and a 2 liter gravity drain to theportal vein. The liver was then disconnected from the OCS and placed ina cold saline bath for 45 minutes.

Final Reperfusion of the Donor Liver (4 hours): The transplantation wasreplicated/simulated by the following process to isolate the graftassessment markers of ischemia and reperfusion due to preservationtechnique from other confounding variables associated with thetransplant model (described above). The liver graft was reperfusedex-vivo in a new OCS liver perfusion module using normothermic freshwhole blood from a different swine at 37° C. for 4 hours. For thesimulated transplant phase, a new perfusion module was used to perfusethe organ on the OCS. The perfusion pressures/flows were controlled tonear physiologic levels and temperature was maintained at 37° C. Theliver was monitored hourly for the same markers as in the preservationperiod. In addition, liver tissue samples were evaluated histologicallyto assess hepatic tissue architecture and any signs of injury in thesame way as described above in Phase I.

Phase II, Simulated Transplant Cold Preservation Control arm (N=6).

This was achieved by replicating all key clinical steps of liverretrieval, preservation and simulated transplantation processes in thefollowing sequence:

Donor Organ Retrieval (30-45 minutes): During this phase, the donororgan was retrieved, for 30-45 minutes to replicate the clinicalcondition of donor liver retrieval. The same prep, organ retrieval,cannulation and pre-OCS flush were performed as described in Phase I.

Donor liver cold preservation: During this phase, the donor liver waspreserved for 8 hours using standard of care cold storage solutionBelzer UW® (UW Solution) for liver flush and storage at 2-5° C. to mimicthe standard of care for liver cold preservation.

Post-cold Preservation, organ flush and preparation (45 minutes): Duringthis phase the donor liver was flushed with cold flush solution usingthe final flush line included in the OCS liver perfusion terminationset. The liver was flushed using 3 L of cold PlasmaLyte solutionsupplemented with Sodium bicarbonate (NaHCO₃) 10 mml/L, EpoprostenolSodium 2 mcg/L and Methylprednisolone 160 mg/L flush, supplying 1 literat ˜50-70 mmHg to the hepatic artery, and a 2 liter gravity drain to theportal vein. The liver was then disconnected from the OCS and placed ina cold saline bath for 45 minutes.

Final Reperfusion of the Donor Liver (4 hours): The transplantation wasreplicated/simulated by the following process to isolate the graftassessment markers of ischemia and reperfusion due to preservationtechnique from other confounding variables associated with thetransplant model (described above). The liver graft was reperfusedex-vivo in a new OCS liver perfusion module using normothermic freshwhole blood from a different swine for 4 hours. The perfusionpressures/flows were controlled to near physiologic levels andtemperature was maintained at 37° C. The liver was monitored hourly forthe same markers as in the preservation period. In addition, livertissue samples were evaluated histologically to assess hepatic tissuearchitecture and any signs of injury in the same way as described abovein Phase I.

The results observed for Phase II, indicate that samples that wereperfused using the OCS system achieved better post-perfusion resultsthan samples that were subjected to cold storage. The samples that weresubject to cold storage, did not meet the acceptance criteria describedpreviously during the 4 hours of simulated transplant, as compared tothe OCS arm of the group.

In the cold storage control arm, the metabolic liver functionsdemonstrated unstable and worsening profile over the course of the 4hours of the simulated transplant as evidenced by the higher andunstable lactate trend, as compared to the OCS arm of the group, whichdemonstrated much better metabolic function, as evidenced by trendingdown arterial lactate. This indicates that the OCS-arm livers hadsignificantly better metabolic function as compared to the cold storagecontrol arm. In the cold storage control arm, the liver enzyme (AST)profile, which is a sensitive marker of liver injury, was unstable andtrending up to much higher levels than the OCS arm of the group. Thisindicates compromised liver functions for liver grafts in the controlarm, as compared to the well persevered and good functioning livergrafts in the OCS arm, which was demonstrated by much lower level ofLiver enzyme (AST) trend in the OCS arm. In the cold storage controlarm, the pH trend required much higher doses of HCO3 to achieve andmaintain a stable metabolic profile, than the doses required for the OCSarm of the group. This indicates that the OCS arm was able to maintain amuch better metabolic profile than the cold storage control arm. Thebile production rate was less in the cold storage control arm than inthe OCS arm. This indicates better liver graft functions in the OCS armas compared to the cold storage control arm. The perfusion parameterswere comparable for both arms of the group. Based on the abovecomparison results, the OCS arm successfully met the protocolpre-specified acceptance criteria while the cold storage control arm didnot meet the identical acceptance criteria.

FIG. 49 depicts Hepatic Artery Flow on a simulated transplant OCS-Liverpreservation arm vs. a simulated transplant control cold preservationarm. As illustrated, the graph of FIG. 49 depicts stable Hepatic ArteryFlow (HAF) over the course of 4 hours of perfusion on the OCS during thesimulated transplant period.

FIG. 50 depicts Portal Vein Flow on a simulated transplant OCS-Liverpreservation arm vs. a simulated transplant control cold preservationarm. As illustrated in FIG. 50, the graph demonstrates Stable PortalVein Flow (PVF) over the course of 4 hours perfusion on the OCS duringthe simulated transplant period.

FIG. 51 depicts Hepatic Artery Pressure vs. Portal Vein Pressure in asimulated transplant OCS-Liver preservation arm vs. a simulatedtransplant control cold preservation arm. The graph of FIG. 51demonstrates a stable Hepatic Artery Pressure (HAP) and Portal VeinPressure (PVP) trend over the course of 4 hours perfusion on the OCS.

FIG. 52 depicts Arterial Lactate on a simulated transplant OCS-Liverpreservation arm vs. a simulated transplant control cold preservationarm. The graph of FIG. 52 demonstrate that the OCS-arm perfused livershad a much better metabolic function, as evidenced by trending downarterial Lactate. This indicates that the OCS-arm livers hadsignificantly better metabolic function as compared to cold stored arm.

FIG. 53 depicts bile production of a simulated transplant OCS-Liverpreservation arm vs. a simulated transplant control cold preservationarm. The graph of FIG. 53 demonstrates that the OCS arm perfused livershad a higher bile production rate as compared to cold stored livers.This indicates better liver graft function in the OCS group vs. a coldstored group.

FIG. 54 depicts a AST Level of simulated transplant OCS-Liverpreservation arm vs. a simulated transplant control cold preservationarm. The graph of FIG. 54 demonstrates that the OCS perfused livers hada significantly lower AST levels throughout the 4 hour simulatedtransplant period. This indicates significantly less liver injury to thegraft in the OCS group as compared to the cold stored group.

FIG. 55 depicts ACT Levels of a simulated transplant OCS-Liverpreservation arm vs. a simulated transplant control cold preservationarm. Activated clotting time (ACT) was maintained above 300 sec over thecourse of 8 hours perfusion on the OCS.

FIG. 56 depicts oncotic pressure of a simulated transplant OCS-Liverpreservation arm vs. a simulated transplant control cold preservationarm. As depicted in FIG. 56, there was stable oncotic pressure on theOCS-Liver preservation arm.

FIG. 57 depicts the Bicarb Level of a simulated transplant OCS-Liverpreservation arm vs. a simulated transplant control cold preservationarm.

FIG. 58 depicts pH Levels of a simulated transplant OCS-Liverpreservation arm vs. a simulated transplant control cold preservationarm. The graph of FIG. 58 demonstrates that an OCS perfused liver hadbetter pH values over the course of 4 hours of perfusion on the OCS ascompared to the cold stored livers. OCS perfused livers needed veryminimal HCO3 correction as compared to the cold stored group, this is anindication of better functioning liver grafts in the OCS arm as comparedto the control arm.

As illustrated in FIG. 59, histological examination of Parenchymaltissue and Bile duct tissue shows normal liver sinusoidal structure withno evidence of necrosis or ischemia and normal bile duct epithelialcells indicating adequate perfusion and lack of ischemic injury.

As illustrated in FIG. 60, histological examination of Parenchymaltissue and Bile duct tissue shows significant hemorrhage and congestionwithin the parenchyma, Interlobular hemorrhage, multifocal wide spreadinterlobular hemorrhage, and Lobular congestion.

C. Phase III

This group of pre-clinical simulated transplant testing was conducted tocompare OCS preserved livers (3 samples) for 12 hours versus control armlivers preserved cold (3 samples) using the standard of care cold liverpreservation solution Belzer UW® (UW Solution) for 12 hours. Both theOCS arm and the cold storage arm were then assessed for 24 hours in asimulated transplant model on the OCS using leukocyte-reduced blood froma different animal. Except for the cold preservation phase, the protocolfor both arms of the group was identical. During the simulatedtransplant phase, organ function and stability were assessed bymonitoring and measuring stable perfusion parameters maintained inpre-specified ranges, bile production, liver biomarkers including AST,ALT, ALP, GGT, and total bilirubin, pH levels, and arterial lactatelevels. After the simulated transplant phase, livers were sampled forhistopathology assessment. The acceptance criteria for this phase wasthe same as the acceptance criteria outlined in phase I.

OCS Arm:

Donor Organ Retrieval: During this phase, the donor organ was retrieved,and cold flushed to replicate the clinical condition of donor liverretrieval and instrumentation on the OCS Liver system. The same prep,organ retrieval, cannulation and pre-OCS flush were performed asdescribed in Phase I.

Donor Liver Preservation on OCS (12 hours): During this phase, the donororgan underwent ex-vivo perfusion and assessment using OCS Liver system.Similar organ preservation was performed for this group as the 8 hourpreservation samples described in phase 1. The prime perfusate wascomposed of 1500-2000 ml RBCs (Haemonetics Cell Saver), 400 ml Albumin25%, 700 ml of PlasmaLyte, Antibiotic (gram positive and gram negative)1 g Cefazolin and 100 mg Levofloxacin, 500 mg of Solu-Medrol, 20 mg,Dexamethasone, 50 mmol Hco3, 1 vial of multivitamin, and 10 ml of Cagluconate (4.65 mEq)

During preservation, 80% O2 was used starting at a rate of 450 ml/minstarting just before organ instrumentation and was adjusted according tothe arterial pCO2 and pO2. Temperature was maintained at 34° C.

Continuous infusion was delivered using the integrated OCS-SDS. Flolanwas added to the HA inflow at 0-20 mic/hr (0-20 ml/hr), as needed (0.05mg Flolan in 50 ml of Flolan Diluent “1 mic/ml”). CLINIMIX E TPN with 30IU of insulin, 25 g of glucose and 40000 U of Heparin added wascontinuously infused to the PV at a rate of 30 mL/h starting withpriming. Na Taurocholic Salt, Gama sterilized Bile salt was infused at arate of 3 mL/h (concentration 1 g/50 ml sterile water) starting withpriming.

Target pressures and flows were: Portal Vein pressure 1-8 mmHg; PortalVein flow 0.7-1.7 L/min; Hepatic Artery pressure 85-110 mmHg; andHepatic artery flow 0.3-0.7 L/min.

Using the Final Flush line included in the OCS Liver perfusiontermination set, the liver was flushed and cooled on the OCS using 3 Lof Cold PlasmaLyte solution, supplying 1 liter at ˜50-70 mmHg to thehepatic artery, and a 2 liter gravity drain to the portal vein. Theliver was then disconnected from the OCS and placed in a cold salinebath for 45 minutes.

Cold Static Preservation Storage Arm:

The same prep, organ retrieval, cannulation and pre-OCS flush wereperformed as described in Phase I.

After flushing the organ with 3 Liters of UW, it was stored cold in UWsolution at temperature ˜5 degree for 12 hours. Using the Final Flushline included in the OCS Liver perfusion termination set, the liver wasflushed and cooled on the OCS using 3 L of Cold PlasmaLyte solution,supplying 1 liter at ˜50-−70 mmHg to the hepatic artery, and a 2 litergravity drain to the portal vein. The liver was then disconnected fromthe OCS and placed in a cold saline bath for 45 minutes.

Both sets of livers were subjected to the post-transplant phase for 24hours, where they were instrumented onto an OCS machine and suppliedwith a post-perfusate solution comprising 1500-3000 ml leukocytesreduced blood, 100 ml Albumin 25%, Antibiotic (gram positive and gramnegative) lg Cefazolin and 100 mg Levofloxacin, 500 mg of Solu-Medrol,20 mg, Dexamethasone, 50 mmol HCO3, 1 vial of multivitamin, and 10 ml ofCa gluconate (4.65 mEq). During simulated transplant, 80% O2 was usedstarting at a rate of 450 ml/min starting just before organinstrumentation and was adjusted according to the arterial pCO2 and pO2.Temperature was maintained at 37° C.

Continuous infusion was delivered using the integrated OCS-SDS. Flolanwas added to the HA inflow at 0-20 mic/hr. (0-20 ml/hr.), as needed(0.05 mg Flolan in 50 ml of Flolan Diluent “1 mic/ml”). CLINIMIX E TPNwith 30 IU of insulin, 25 g of glucose and 40000 U of Heparin added wascontinuously infused to the PV at a rate of 30 mL/h starting withpriming. Na Taurocholic Salt, Gama sterilized Bile salt was infused at arate of 3 mL/h (concentration 1 g/50 ml sterile water) starting withpriming.

Target pressures and flows were: Portal Vein pressure 1-8 mmHg; PortalVein flow 0.7-1.7 L/min; Hepatic Artery pressure 85-110 mmHg; andHepatic artery flow 0.3-0.7 L/min.

Using the Final Flush line included in the OCS Liver perfusiontermination set, the liver was flushed and cooled on the OCS using 3 Lof Cold PlasmaLyte solution, supplying 1 liter at ˜50-70 mmHg to thehepatic artery, and a 2 liter gravity drain to the portal vein. EachLiter will be supplemented by 10 mmol HCO3 and 150 mg of Solu-Medrol.The liver was then disconnected from the OCS and placed in a cold salinebath for 45 minutes. Table 9 below illustrates the liver perfusateinfusions and rate.

TABLE 9 OCS liver perfusate infusions and rate Dose Continuous InfusionMix Total parenteral nutrition (TPN) Mix: 30 ml/hr CLINIMIX E TPN (4.25%Amino Acid/10% Dextrose); PLUS Insulin 30 IU Glucose 20 gms Heparin40,000 units As Needed Additives Prostacyclin infusion as needed tocontrol Hepatic 0-20 mics/hr artery pressure - e.g. Epoprostenol Sodium0.5 mg Bile Salts 0-10 ml/hr e.g. Taurocholic acid sodium (1 gm/50 ml)NaHCO3 8.4% to correct metabolic acidosis 1.5 mEq/1 base excess

FIG. 61 is a samples location diagram illustrating locations of samplesfrom a liver of a pig.

The following liver histopathology sampling protocol was followed toassess the sample livers.

Samples Collection Time:

At completion of the experiment (at the end of the 24 hr simulatedtransplant phase).

Method and Samples Collected:

1. Gross Picture: photographs of capsular and under surface of the OCSand CS livers at the beginning of the gross examination post study.2. Bile Duct: entire extra-hepatic bile duct and as much adherentsurrounding tissue (not surgically dissected from the surroundingtissue) in a neutral-buffered formalin jar.3. Electron Microscopy (EM): 0.1 cm (1 mm) fragment of the liver tissuefrom the peripheral and deep aspect of the Left Lateral Lobe and theRight Medial Lobe. Place the tissue specimen in electron microscopyfixative.4. Hepatic Parenchyma (LM): 1×1 cm sections obtained from the peripheryand deep aspects of each lobe (total of 8), and preserved in Formalin.Sections thickness no more than 3-5 mm and fixative volume 15-20 timeshigher than the specimen volume. Any obvious defect was sampled.

Samples Locations:

Two samples were collected from each lobe according to the FIG. 61 toaccess the hepatic parenchyma, each sample will be preserved in separatejar filled with 10% formalin and labeled accordingly.

1. Left Lateral Lobe Peripheral—LM (LLLP—LM) 2. Left Lateral LobePeripheral—EM (LLLP—EM) 3. Left Lateral Lobe Deep—LM (LLLD—LM) 4. LeftLateral Lobe Deep—EM (LLLD—EM) 5. Left Medial Lobe Peripheral—LM(LMLP—LM) 6. Left Medial Lobe Deep—LM (LMLD—LM) 7. Right Medial LobePeripheral—LM (RMLP—LM) 8. Right Medial Lobe Peripheral—EM (RMLP—EM) 9.Right Medial Lobe Deep—LM (RMLD—LM) 10. Right Medial Lobe Deep—EM(RMLD—EM) 11. Right Lateral Lobe Peripheral—LM (RLLP—LM) 12. RightLateral Lobe Deep—LM (RLLD—LM) 13. Extra—Hepatic Bile Duct (EHBD)

Data Collection and Analysis

Preservation data was summarized in tabular and graphic form, dependingon the variable. Then continuous variables were analyzed with means,medians, standard deviations, and minimum and maximum values. Afterthat, AST, ALT, GGT, ALP test results were collected, recorded andattached. Next, arterial lactate was collected, recorded and attached.pH was then measured, recorded and attached. HCO3 levels were thenmeasured, recorded and attached. Lastly, total bile produced volume wascollected and recorded.

Results of Phase III.

The OCS arm (N=3) of this group successfully met all of the acceptancecriteria, which was pre-specified in the protocol, by demonstrating thefollowing throughout the 24 hours of the simulated transplant phase:Stable perfusion parameters throughout preservation on the OCS for HAF,HAP, PVF and PVP, stable or trending down arterial lactate, continuousbile production with a rate of >10 ml/hr., stable or trending down liverenzymes (AST), and normal and stable perfusate PH. For example, FIG. 62illustrates the Hepatic Artery Pressure (HAP) trend over the course of24 hours perfusion on the OCS.

FIG. 63 illustrates the Portal Vein Pressure in an OCS-LiverPreservation arm vs the control Cold preservation arm. FIG. 63demonstrates the Portal Vein Pressure (PVP) trend over the course of 24hours perfusion on the OCS; the cold preservation arm demonstrated anincrease in the PVP over time compared to stable PVP for the OCSpreservation arm.

FIG. 64 illustrates a Hepatic Artery Flow in a OCS-Liver Preservationarm vs. control Cold preservation arm. FIG. 64 demonstrates stableHepatic Artery Flow (HAF) trend over the course of 24 hours perfusion onthe OCS.

FIG. 65 illustrates a Portal Vein Flow in an OCS-Liver Preservation armvs. control Cold preservation arm. FIG. 65 demonstrates stable PortalVein Flow (PVF) trend over the course of 24 hours perfusion on the OCS.

In comparison, the simulated transplant OCS arm (N=3) performed betterthan the control arm. The perfusion parameters were comparable for botharms of the group however the control arm vascular resistance was highercompared to the OCS arm. The control arm had a much higher peak of theLactate level at 7.8 mmol/L compared to 2.4 mmol/L for the OCS arm. Botharms continued to produce bile throughout the simulated transplant phaseat a rate >10 ml/hr. For example, FIG. 66 depicts Arterial Lactate in anOCS-Liver Preservation arm vs. a control Cold preservation arm. FIG. 66demonstrates Arterial Lactate in an OCS-Liver Preservation arm vs.control Cold preservation arm. This indicates that the OCS-arm livershad significantly better metabolic function as compared to cold storedarm.

Liver enzymes which is a sensitive biomarker of Liver injury (AST, ALT,and the GGT) showed a much higher peaks compared to the OCS arm of thegroup. Average AST peak was 88.7 in the OCS arm compared to 1188 for thecontrol arm. Average ALT levels peaked at 31.3 for the OCS arm comparedto a peak of 82 for the control arm. Average GGT levels peaked at 28.7for the OCS arm compared to 97 for the control arm. This indicates wellpreserved Livers and less cell injury for Liver grafts preserved on theOCS arm as compared to the control arm. For example, FIG. 67 illustratesan AST Level OCS-Liver Preservation arm vs. control Cold Preservationarm. FIG. 67 demonstrates that the OCS perfused livers had significantlylower AST levels throughout the 24 hours simulated transplant period.This indicates significantly less liver injury to the graft in the OCSgroup as compared to the cold stored group.

FIG. 68 illustrates an ALT Level OCS-Liver Preservation arm vs. controlCold preservation arm. FIG. 68 demonstrates that the OCS perfused livershad lower ALT levels with an average peak at 31.3 compared to averagepeak of 82 for the control group. This indicates less liver injury tothe graft in the OCS arm as compared to the control cold stored arm.

FIG. 69 depicts a GGT Level of an OCS-Liver Preservation arm vs. controlCold preservation arm. FIG. 69 demonstrates that the OCS perfused livershad a much lower GGT levels throughout the 24 hr. period. This indicatesbetter hepatobilliary protection of the graft in the OCS arm as comparedto the control cold stored arm.

The OCS arm demonstrated better metabolic profile compared to thecontrol arm as manifested by the stable and normal pH levels compared toa lower pH for the control arm. This indicates that the OCS arm was ableto maintain a much better metabolic profile than the control arm. Forexample, FIG. 70 depicts a pH level of an OCS-Liver Preservation arm vs.a control Cold preservation arm. As demonstrated by FIG. 70, OCSperfused livers had normal and stable pH values over the course of 24hours of perfusion as compared to the Control cold preservation armlivers.

Also the OCS arm demonstrated better metabolic Liver functions as shownby higher HCO3 levels over the course of the 24 hours of the simulatedtransplant, as compared to the control arm of the group, whichdemonstrated lower HCO3 throughout the simulated transplant phase. Thisindicates that the OCS-arm livers had better metabolic function ascompared to the control arm. For example, FIG. 71 depicts a HCO3 levelin an OCS-Liver Preservation arm vs. a Control Cold preservation arm. Asillustrated in FIG. 71, OCS perfused livers had higher HCO3 levels overthe course of 24 hours of perfusion as compared to the Control coldpreservation arm livers.

FIG. 72 depicts a bile production OCS-Liver Preservation arm vs. controlCold preservation arm. FIG. 72 demonstrates that both arms maintainedbile production rate of >10 ml/hr. Based on the above presented data,The OCS has demonstrated stable perfusion and metabolic profile withwell-preserved liver graft functions for up to 12 hours of OCSpreservation. In addition, when compared to the control arm of coldstatic preservation, in the simulated transplant model, the OCS perfusedswine livers demonstrated a significantly better metabolic function, asevidenced by their ability to metabolize lactate to baseline levels ascompared to cold stored livers where lactate continued to rise tosignificantly higher levels. Additionally, the OCS perfused swine livershad significantly lower AST levels as compared to the much higher levelof AST in the simulated transplant control arm, which indicates betterLiver graft functions in the OCS arm as compared to the control coldstored arm. The results of this pre-clinical OCS Liver device testingdemonstrated that the OCS device is safe and effective in preservationof swine livers, as evidenced by meeting the specified acceptancecriteria. The differences observed between the control arm and the OCSarm in Phase III were similar to the differences observed in Phase II,indicating that the OCS arm had better results. Additional uses

While preservation of a donor organ which is intended fortransplantation has been described above, some embodiments of the organcare system 600 described herein can be used for other purposes. Forexample, the system 600 can also be used for maintaining an organ duringreconstructive or other types of surgery, therapy, and/or treatment(e.g., complicated, high-risk surgeries and/or treatments). That is,some surgeries, therapies, and/or treatments can be damaging to thehuman body, if the procedure were performed on an in vivo organ. Thus,it can be beneficial to remove the organ from the patient's body,perform surgery on and/or treat the organ ex vivo, and then reimplantthe organ back into the patient's body. For example, certain radiationtherapies can be damaging to tissue surrounding the organ. Thus, byremoving the organ, intensive radiation therapy can be performed on theorgan without collateral damage to the patient's body. Other embodimentsare possible.

D. Ex-Vivo Treatment of Diseased Livers, Including Cancer, Fatty Livers,Infection, by Delivery of Therapeutics to Organ

In some embodiments, the liver preserved on the organ care system 600can be subjected to ex-vivo therapeutic treatment of liver diseases.Non-limiting examples of liver diseases include cancer, fatty livers,and liver infection. The therapy can be conducted by adding therapeuticagents to the perfusion fluid circulating through the organ care system600, thereby providing it to the liver itself. Alternatively, thetherapeutic agents can be directly added into one or more nutritionalsolution described herein. In some embodiments, the temperature of theperfusion fluid and/or liver can be maintained at 40° C. or 42° C.,which can accelerate the rate of breakdown and dissolution of fattycells in the liver.

Non-limiting examples of anti-cancer therapeutic agents suitable forex-vivo therapeutic treatment of liver cancer include microtubulebinding agents, DNA intercalators or cross-linkers, DNA synthesisinhibitors, DNA and/or RNA transcription inhibitors, antibodies,enzymes, enzyme inhibitors, gene regulators, and/or angiogenesisinhibitors. Anti-cancer “Microtubule binding agent” refers to an agentthat interacts with tubulin to stabilize or destabilize microtubuleformation thereby inhibiting cell division. Examples of microtubulebinding agents include, without limitation, paclitaxel, docetaxel,vinblastine, vindesine, vinorelbine (navelbine), the epothilones,colchicine, dolastatin 15, nocodazole, podophyllotoxin and rhizoxin.Analogs and derivatives of such compounds also can be used and will beknown to those of ordinary skill in the art.

Anti-cancer DNA and/or RNA transcription regulators include, withoutlimitation, actinomycin D, daunorubicin, doxorubicin and derivatives andanalogs thereof. DNA intercalators and cross-linking agents include,without limitation, cisplatin, carboplatin, oxaliplatin, mitomycins,such as mitomycin C, bleomycin, chlorambucil, cyclophosphamide andderivatives and analogs thereof. DNA synthesis inhibitors include,without limitation, methotrexate, 5-fluoro-5′-deoxyuridine,5-fluorouracil and analogs thereof. Examples of suitable enzymeinhibitors include, without limitation, camptothecin, etoposide,formestane, trichostatin and derivatives and analogs thereof. Otheranti-tumor agents can include adriamycin, apigenin, rapamycin,zebularine, cimetidine, and derivatives and analogs thereof. Any othersuitable liver cancer therapeutic agents known in the art arecontemplated.

A further advantage of the chemotherapy described above is itsspecificity: the anticancer agent is specifically delivered to thediseased organ, the liver, without any undesirable toxicity to otherhealthy organs or tissues.

Non-limiting examples of therapeutic agents suitable for ex vivotherapeutic treatment of fatty liver disease include pioglitazone,rosiglitazone, orlistat, ursodiol, and betaine. Any other suitable fattyliver therapeutic agents known in the art are contemplated.

Non-limiting examples of therapeutic agents suitable for ex-vivotherapeutic treatment of liver infection include terferon alfa-2b,terferon alfa-2a, ribavirin, telaprevir, boceprevir, simeprevir, andsofobuvir. Any other suitable liver infection therapeutic agents knownin the art are contemplated.

E. Regenerative Approaches Including Stem Cell or Gene Delivery

In other embodiments, the organ preserved by the organ care system 600described herein can be subjected to regenerative treatments.Non-limiting examples of the organ regenerative treatments include stemcell therapy or gene delivery therapy. Stem cells are undifferentiatedbiological cells that can differentiate into specialized cells, e.g.,hepatocytes. Adult stem cells can be harvested from blood, adipose, andbone marrow of the donor of the liver with various types of liverdiseases, or of another adult with compatible stem cells (stem cellstransplantation). The isolated stem cells, e.g., bone marrow cells, canbe used to infuse the damaged or diseased liver preserved on the organcare system 600 to repair the liver to a healthier state. For instance,the isolated stem cells can be isolated from the donor and included inthe blood product in the perfusion fluid.

In some other embodiments, the liver preserved by the organ care system600 described herein can be subjected to gene delivery therapy. Genedelivery is the process of introducing foreign DNA into host cells,e.g., liver cells, to effect treatment of diseases. In certainembodiments, the gene delivery therapy is virus-mediated gene deliveryutilizing a virus to inject its DNA inside the liver cells. Non-limitingexamples of suitable viruses include retrovirus, adenovirus,adeno-associated virus and herpes simplex virus. In some embodiments, agene that is used to treat certain liver diseases is packaged into avector (virus or other) and included as part of the perfusion fluid toperfuse the liver or added to the circulation of the organ care system600 directly.

F. Ex-Vivo Immune Modulation

In other embodiments, the donor's liver preserved by the organ caresystem 600 described herein can be subjected to immune regulations.Immune responses and their modulation within the liver can affect theoutcome liver transplantation. More importantly, a liver disease can betreated by inducing, enhancing, or suppressing an immune response fromthe liver. For instance, the liver immune system can be activated toattack malicious tissues to treat liver cancer. On the other hand, theliver immune system can be suppressed to treat autoimmune liver diseasesuch as autoimmune hepatitis. Any immunosuppressive agents or immuneactivating agents known in the art can be used to treat the preservedliver to achieve the desirable effect.

G. Ex-Vivo Surgical Treatment of Livers

In yet other embodiments, the donor's liver preserved by the organ caresystem 600 described herein can be subjected to surgical treatment suchas liver tumor resection or split transplant where the liver is dividedbetween two recipient patients. In yet other embodiments, the donor'sliver preserved by the organ care system 600 described herein can besubjected to irradiation therapy to treat certain liver diseases such asliver cancer.

XI. CONCLUSION

Other embodiments are within the scope and spirit of the disclosedsubject matter. In some embodiments, a perfusion circuit for perfusing aliver ex-vivo is disclosed, which comprises a pump for providingpulsatile fluid flow of a perfusion fluid through the circuit, a gasexchanger, a divider in fluid communication with the pump configured todivide the perfusion fluid flow into a first branch and a second branchwherein the first branch comprises a hepatic artery interface whereinthe first branch is configured to provide a first portion of theperfusion fluid to a hepatic artery of the liver at a high pressure andlow flow rate via the hepatic artery interface wherein the first branchis in fluid pressure communication with the pump wherein the secondbranch comprises a portal vein interface wherein the second branch isconfigured to provide a second portion of the perfusion fluid to aportal vein of the liver at a low pressure and high flow rate via theportal vein interface the second branch further comprising a clamplocated between the divider and the portal vein interface forselectively controlling the flow rate of perfusion fluid to the portalvein the second branch further comprising a compliance chamberconfigured to reduce the pulsatile flow characteristics of the perfusionfluid from the pump to the portal vein wherein the pump is configured tocommunicate fluid pressure through the first and second branches to theliver, a drain configured to receive perfusion fluid from anuncannulated inferior vena cava of the liver, and a reservoir positionedbelow the liver and located between drain and the pump, configured toreceive the perfusion fluid from the drain and store a volume of fluid.

In certain embodiments, the second branch of a perfusion circuitcomprises a plurality of compliance chambers. In certain embodiments, acompliance chamber in a perfusion circuit is located between the dividerand the portal vein interface. In certain embodiments, a portal veininterface of a perfusion circuit has a larger cross sectional area thana hepatic artery interface. In certain embodiments, a perfusion circuitincludes at least one flow rate sensor in a second branch, and at leastone pressure sensor. In certain embodiments, a pump comprises a pumpdriver, and the position of the pump driver is adjustable to control thepattern of pulsatile flow to a liver. In some embodiments a clampcomprises an engaged position and a disengaged position, the clamp maybe adjusted to select the desired clamping force and corresponding flowrate when the clamp is in the disengaged position, the clamp may bemoved to the engaged position to apply the selected clamping forcewithout further adjustment when in the engaged position, such that auser may quickly engage and disengage the clamp while still havingprecise control over the amount of clamping force applied to theperfusion circuit.

In some embodiments, a system for perfusing an ex vivo liver at nearphysiologic conditions is disclosed, the system comprising a perfusioncircuit comprising a pump for pumping perfusion fluid through thecircuit, the pump in fluid communication with a hepatic artery interfaceand a portal vein interface, wherein the pump provides perfusion fluidto a hepatic artery of the liver at a high pressure and low flow ratevia the hepatic artery interface; and wherein the pump providesperfusion fluid to the a portal vein of the liver at a low pressure andhigh flow rate via the portal vein interface, a gas exchanger, a heatingsubsystem for maintaining the temperature of the perfusion fluid at anormothermic temperature, a drain configured to receive the perfusionfluid from an inferior vena cava of the liver, a reservoir configured toreceive perfusion fluid from the drain and store a volume of fluid. Insome embodiments, a heating subsystem is configured to maintain theperfusion fluid at a temperature between 34-37° C. In some embodiments,a the perfusion circuit comprises an inferior vena cava cannula. In someembodiments, a control system for controlling operation of the system isdisclosed, comprising an onboard computer system connected to one ormore of the components in the system, a data acquisition subsystemcomprising at least one sensor for obtaining data relating to the organ,and a data management subsystem for storing and maintaining datarelating to operation of the system and with respect to the liver. Insome embodiments, a heading subsystem comprises a dual feedback loop forcontrolling the temperature of the perfusion fluid within the system.

In some embodiments, a system for preserving a liver ex vivo atphysiologic conditions is disclosed, comprising a multiple use modulecomprising a pulsatile pump, a single use module comprising, a perfusioncircuit configured to provide perfusion fluid to the liver, a pumpinterface assembly for translating pulsatile pumping from the pump tothe perfusion fluid, a hepatic artery interface configured to deliverperfusion fluid to a hepatic artery of the liver, a portal veininterface configured to deliver perfusion fluid to a portal vein of theliver, a divider to supply perfusion fluid flow from the pump interfaceassembly to the hepatic artery interface at a high pressure and low flowrate and to the portal vein interface at a low pressure and high flowrate, an organ chamber assembly configured to hold an ex vivo organ, theorgan chamber assembly including a housing, a flexible support surfacesuspended within the organ chamber assembly, and a bile containerconfigured to collect bile produced by the liver.

In some embodiments, flexible support surface is configured to conformto differently sized organs, and further comprising projections tostabilize the liver in the organ chamber assembly. In some embodiments,a flexible support surface comprises a top layer, a bottom layer, and adeformable metal substrate positioned between the top layer and thebottom layer. In some embodiments, a flexible support surface isconfigured to cradle and controllably support a liver without applyingundue pressure to the liver. In some embodiments, a single use modulecomprises a wrap configured to cover the liver in the organ chamberassembly. In some embodiments, a single use module comprises a sensor tomeasure the volume of bile collected in the bile container. In someembodiments, a single use module can be sized and shaped forinterlocking with a portable chassis of the multiple use module forelectrical, mechanical, gas and fluid interoperation with the multipleuse module. In some embodiments, multiple and single use modules cancommunicate with each other via an optical interface, which comes intooptical alignment automatically upon the single use disposable modulebeing installed into the portable multiple use module.

The subject matter described herein can be implemented using digitalelectronic circuitry, or in computer software, firmware, or hardware,including the structural means disclosed in this specification andstructural equivalents thereof, or in combinations of them. The subjectmatter described herein can be implemented as one or more computerprogram products, such as one or more computer programs tangiblyembodied in an information carrier (e.g., in a machine-readable storagedevice), or embodied in a propagated signal, for execution by, or tocontrol the operation of, data processing apparatus (e.g., aprogrammable processor, a computer, or multiple computers). A computerprogram (also known as a program, software, software application, orcode) can be written in any form of programming language, includingcompiled or interpreted languages, and it can be deployed in any form,including as a stand-alone program or as a module, component,subroutine, or other unit suitable for use in a computing environment. Acomputer program does not necessarily correspond to a file. A programcan be stored in a portion of a file that holds other programs or data,in a single file dedicated to the program in question, or in multiplecoordinated files (e.g., files that store one or more modules,sub-programs, or portions of code). A computer program can be deployedto be executed on one computer or on multiple computers at one site ordistributed across multiple sites and interconnected by a communicationnetwork.

The processes and logic flows described in this specification, includingthe method steps of the subject matter described herein, can beperformed by one or more programmable processors executing one or morecomputer programs to perform functions of the subject matter describedherein by operating on input data and generating output. The processesand logic flows can also be performed by, and apparatus of the subjectmatter described herein can be implemented as, special purpose logiccircuitry, e.g., an FPGA (field programmable gate array) or an ASIC(application-specific integrated circuit).

Processors suitable for the execution of a computer program include, byway of example, both general and special purpose microprocessors, andany one or more processor of any kind of digital computer. Generally, aprocessor will receive instructions and data from a read-only memory ora random access memory or both. The essential elements of a computer area processor for executing instructions and one or more memory devicesfor storing instructions and data. Generally, a computer will alsoinclude, or be operatively coupled to receive data from or transfer datato, or both, one or more mass storage devices for storing data, e.g.,magnetic, magneto-optical disks, or optical disks. Information carrierssuitable for embodying computer program instructions and data includeall forms of non-volatile memory, including by way of examplesemiconductor memory devices, (e.g., EPROM, EEPROM, and flash memorydevices); magnetic disks, (e.g., internal hard disks or removabledisks); magneto-optical disks; and optical disks (e.g., CD and DVDdisks). The processor and the memory can be supplemented by, orincorporated in, special purpose logic circuitry.

To provide for interaction with a user, the subject matter describedherein can be implemented on a computer having a display device, e.g., aCRT (cathode ray tube) or LCD (liquid crystal display) monitor, fordisplaying information to the user and a keyboard and a pointing device,(e.g., a mouse or a trackball), by which the user can provide input tothe computer. Other kinds of devices can be used to provide forinteraction with a user as well. For example, feedback provided to theuser can be any form of sensory feedback, (e.g., visual feedback,auditory feedback, or tactile feedback), and input from the user can bereceived in any form, including acoustic, speech, or tactile input.

The techniques described herein can be implemented using one or moremodules. As used herein, the term “module” refers to computing software,firmware, hardware, and/or various combinations thereof. At a minimum,however, modules are not to be interpreted as software that is notimplemented on hardware, firmware, or recorded on a non-transitoryprocessor readable recordable storage medium (i.e., modules are notsoftware per se). Indeed “module” is to be interpreted to always includeat least some physical, non-transitory hardware such as a part of aprocessor or computer. Two different modules can share the same physicalhardware (e.g., two different modules can use the same processor andnetwork interface). The modules described herein can be combined,integrated, separated, and/or duplicated to support variousapplications. Also, a function described herein as being performed at aparticular module can be performed at one or more other modules and/orby one or more other devices instead of or in addition to the functionperformed at the particular module. Further, the modules can beimplemented across multiple devices and/or other components local orremote to one another. Additionally, the modules can be moved from onedevice and added to another device, and/or can be included in bothdevices.

The subject matter described herein can be implemented in a computingsystem that includes a back-end component (e.g., a data server), amiddleware component (e.g., an application server), or a front-endcomponent (e.g., a client computer having a graphical user interface ora web browser through which a user can interact with an implementationof the subject matter described herein), or any combination of suchback-end, middleware, and front-end components. The components of thesystem can be interconnected by any form or medium of digital datacommunication, e.g., a communication network. Examples of communicationnetworks include a local area network (“LAN”) and a wide area network(“WAN”), e.g., the Internet.

What is claimed is:
 1. A perfusion circuit for perfusing a liver ex-vivocomprising: a pump for providing pulsatile fluid flow of a perfusionfluid through the circuit; a gas exchanger; a divider in fluidcommunication with the pump configured to divide the perfusion fluidflow into a first branch and a second branch; wherein the first branchcomprises a hepatic artery interface; wherein the first branch isconfigured to provide a first portion of the perfusion fluid to ahepatic artery of the liver at a high pressure and low flow rate via thehepatic artery interface; wherein the first branch is in fluid pressurecommunication with the pump; wherein the second branch comprises aportal vein interface; wherein the second branch is configured toprovide a second portion of the perfusion fluid to a portal vein of theliver at a low pressure and high flow rate via the portal veininterface; the second branch further comprising a clamp located betweenthe divider and the portal vein interface for selectively controllingthe flow rate of perfusion fluid to the portal vein; the second branchfurther comprising a compliance chamber configured to reduce thepulsatile flow characteristics of the perfusion fluid from the pump tothe portal vein; wherein the pump is configured to communicate fluidpressure through the first and second branches to the liver; a drainconfigured to receive perfusion fluid from an inferior vena cava of theliver; and a reservoir positioned below the liver and located betweendrain and the pump, configured to receive the perfusion fluid from thedrain and store a volume of fluid.
 2. The perfusion circuit of claim 1,wherein the second branch comprises a plurality of compliance chambers.3. The perfusion circuit of claim 1, wherein the compliance chamber islocated between the divider and the portal vein interface.
 4. Theperfusion circuit of claim 1, wherein the portal vein interface has alarger cross sectional area than the hepatic artery interface.
 5. Theperfusion circuit of claim 1 further comprising at least one flow ratesensor in the second branch, and at least one pressure sensor.
 6. Theperfusion circuit of claim 1, wherein the pump comprises a pump driver,and wherein the position of the pump driver is adjustable to control thepattern of pulsatile flow to the liver.
 7. The perfusion circuit ofclaim 1, wherein the clamp comprises an engaged position and adisengaged position; wherein the clamp may be adjusted to select thedesired clamping force and corresponding flow rate when the clamp is inthe disengaged position; wherein the clamp may be moved to the engagedposition to apply the selected clamping force without further adjustmentwhen in the engaged position, such that the user may quickly engage anddisengage the clamp while still having precise control over the amountof clamping force applied to the perfusion circuit.
 8. A system forperfusing an ex vivo liver at near physiologic conditions comprising: aperfusion circuit comprising: a pump for pumping perfusion fluid throughthe circuit; the pump in fluid communication with a hepatic arteryinterface and a portal vein interface; wherein the pump providesperfusion fluid to a hepatic artery of the liver at a high pressure andlow flow rate via the hepatic artery interface; and wherein the pumpprovides perfusion fluid to the a portal vein of the liver at a lowpressure and high flow rate via the portal vein interface; a gasexchanger; a heating subsystem for maintaining the temperature of theperfusion fluid at a normothermic temperature; a drain configured toreceive the perfusion fluid from an inferior vena cava of the liver; areservoir configured to receive perfusion fluid from the drain and storea volume of fluid.
 9. The system of claim 8, wherein the heatingsubsystem is configured to maintain the perfusion fluid at a temperaturebetween 34-37° C.
 10. The system of claim 8, wherein the perfusioncircuit further comprises an inferior vena cava cannula.
 11. The systemof claim 8, further comprising a control system for controllingoperation of the system: an onboard computer system connected to one ormore of the components in the system; a data acquisition subsystemcomprising at least one sensor for obtaining data relating to the organ;and a data management subsystem for storing and maintaining datarelating to operation of the system and with respect to the liver. 12.The system of claim 8, wherein the heating subsystem further comprisinga dual feedback loop for controlling the temperature of the perfusionfluid within the system.
 13. A system for preserving a liver ex vivo atphysiologic conditions comprising: a multiple use module comprising apulsatile pump; a single use module comprising; a perfusion circuitconfigured to provide perfusion fluid to the liver; a pump interfaceassembly for translating pulsatile pumping from the pump to theperfusion fluid; a hepatic artery interface configured to deliverperfusion fluid to a hepatic artery of the liver; a portal veininterface configured to deliver perfusion fluid to a portal vein of theliver; a divider to supply perfusion fluid flow from the pump interfaceassembly to the hepatic artery interface at a high pressure and low flowrate and to the portal vein interface at a low pressure and high flowrate; an organ chamber assembly configured to hold an ex vivo organ, theorgan chamber assembly including a housing; a flexible support surfacesuspended within the organ chamber assembly; and a bile containerconfigured to collect bile produced by the liver.
 14. The system ofclaim 13, wherein the flexible support surface is configured to conformto differently sized organs, and further comprising projections tostabilize the liver in the organ chamber assembly.
 15. The system ofclaim 13, wherein the flexible support surface comprises a top layer, abottom layer, and a deformable metal substrate positioned between thetop layer and the bottom layer.
 16. The system of claim 13, wherein theflexible support surface is configured to cradle and controllablysupport the liver without applying undue pressure to the liver.
 17. Thesystem of claim 13, wherein the single use module further comprises awrap configured to cover the liver in the organ chamber assembly. 18.The system of claim 13, wherein the single use module further comprisesa sensor to measure the volume of bile collected in the bile container.19. The system of claim 13, wherein the single use module can be sizedand shaped for interlocking with a portable chassis of the multiple usemodule for electrical, mechanical, gas and fluid interoperation with themultiple use module.
 20. The system of claim 13 wherein the multiple andsingle use modules can communicate with each other via an opticalinterface, which comes into optical alignment automatically upon thesingle use disposable module being installed into the portable multipleuse module.